Substituted quinazoline sulfonamides as thioredoxin interacting protein (TXNIP) inhibitors

ABSTRACT

In one aspect, compounds and compositions that inhibit TXNIP expression and/or that lower hepatic glucose production and methods of identifying, making, and using same are disclosed. The disclosed compounds and compositions can be useful for disorders associated with elevated TXNIP and/or elevated glucagon levels such as, for example, diabetes and associated disorders. Further provided are methods for treating hyperlipidemia or fatty liver disease, optionally associated with elevated TXNIP and/or elevated glucagon levels. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO PRIORITY APPLICATION

This application is a continuation of U.S. application Ser. No.16/470,074 filed Jun. 14, 2019, which is a national phase applicationunder 35 U.S.C. § 371 of International Application No. PCT/US2018/058356filed Oct. 31, 2018, which claims priority to U.S. ProvisionalApplication No. 62/579,594, filed Oct. 31, 2017, the entire contents ofeach being incorporated herein by reference.

STATEMENT REGARDING FEDERALLY FUNDED RESEARCH

This invention was made with government support under grant numberUC4DK104204 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

REFERENCE TO SEQUENCE LISTING

The official copy of the sequence listing is submitted electronicallyvia EFS-Web as an ASCII formatted sequence listing in a file namedUAB_189US2_Seq_List.txt, created on Jul. 12, 2021, having a size of 2 KBand filed concurrently with the specification. The sequence listingcontained in this ASCII formatted document is part of the specificationand is herein incorporated by reference in its entirety.

BACKGROUND

Pancreatic β-cell dysfunction and death play a central role in thedevelopment and progression of diabetes and can be caused by multiplestressors including glucotoxicity, (gluco-)lipotoxicity, and cytokinetoxicity (Poitout and Robertson (2002) Endocrinology 143: 339-342;Eizirik and Mandrup-Poulsen (2001) Diabetologia 44: 2115-2133).Glucotoxicity induced by chronic exposure of β-cells to high levels ofglucose promotes β-cell apoptosis and, combined with the elevatedglucagon levels associated with diabetes (Unger and Orci (1975) Lancet1: 14-16), results in a vicious cycle with further worsening of thehyperglycemia (Poitout and Robertson (2002) Endocrinology 143: 339-342).It was previously shown that thioredoxin-interacting protein (TXNIP), aubiquitously expressed cellular redox regulator (Nishiyama et al. (1999)J. Biol. Chem. 274: 21645-21650), is the top glucose-induced gene in ahuman islet gene expression microarray study (Shalev et al. (2002)Endocrinology 143:3695-98.) and that TXNIP is a crucial mediator ofglucotoxicity-induced β-cell apoptosis (Chen et al. (2008) Diabetes 57:938-44). It was further shown that β-cell TXNIP transcription isupregulated by glucose and its expression is increased in diabetes (Minnet al. (2005) Endocrinology 146:2397-2405.) Also, TXNIP-induced β-celldeath is mediated by the intrinsic/mitochondrial death pathway (Chen etal. (2010) Diabetes 59: 440-447). Further, elevated TXNIP levels alsocontribute to β-cell dysfunction by inducing microRNA expression(miR-204), which in turn targets the insulin transcription factor MafAand thereby inhibits insulin production (Xu et al. (2013) Nat. Med. 19:1141-1146). Conversely, TXNIP deficiency led to an increase infunctional β-cell mass and protected against diabetes in mouse models oftype 1 (T1D) and type 2 (T2D) diabetes (Chen et al. (2008) FASEB J. 22:3581-3594). In addition, TXNIP deletion has been associated with reducedhepatic glucose production and beneficial effects in extrapancreatictissues such as kidney, retina and the cardiovascular system in thecontext of diabetes. Despite the detrimental effects elevated TXNIPplays in diabetes and its associated disorders, prior to the presentdisclosure there was no known effective way to specifically block TXNIPexpression.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompositions and methods for use in the prevention and treatment ofdisorders associated with elevated TXNIP and/or elevated glucagonlevels, such as, for example, diabetes and associated disorders (e.g.,Type 1 diabetes, Type 2 diabetes, gestational diabetes, impaired glucosecontrol, impaired glucose tolerance or pre-diabetes, insulin resistance,hyperlipidemia, non-alcoholic fatty liver disease, complications ofdiabetes, including diabetes-related nephropathy, neuropathy,retinopathy, cardiomyopathy, and cardiovascular disease, as well aspancreatic β-cell loss or pancreatic islet dysfunction, includingdysregulation of insulin and/or glucagon production or secretion) orother disorders associated with endoplasmic reticulum stress and/oroxidative stress of the cell. Additionally, the compositions and methodsare useful in preparing islets for transplantation and/or for treating atransplant recipient.

Disclosed is a method for treating a disorder associated with elevatedTXNIP or elevated glucagon in a mammal, the method comprising the stepof administering to the mammal a therapeutically effective amount of atleast one compound having a structure represented by a formula selectedfrom:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed is a method for inhibiting TXNIP expression or loweringglucagon levels in a mammal, the method comprising the step ofadministering to the mammal an effective amount of at least one compoundhaving a structure represented by a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed herein are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹,when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, andis substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen, —OH, C1-C4alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein each occurrence ofR^(8a) and R^(8b), when present, is independently hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein p is 1 and each of R^(8a)and R^(8b) together comprise ═O; and wherein R⁹ is hydrogen, C1-C4alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino, or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy),—(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), and R^(5d) is independently hydrogen, halogen, —NH₂,—CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R^(5c) is hydrogen,halogen, —NH₂, —OH, —CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), orCHR^(6b); wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b)is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ ishydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;provided that when R^(5b) is morpholinyl and R¹ is thiophenyl orthiazolyl, then q is 1 and at least one of R^(5a), R^(5c), and R^(5d) isnot hydrogen, or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed are compounds having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or1; wherein R¹ is —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen, —OH, C1-C4alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; and wherein each occurrence ofR⁸ and R^(8b), when present, is independently hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein p is 1 and each of R^(8a)and R^(8b) together comprise ═O; provided that when R¹ is methyl andeach of R³ and R⁴ is hydrogen then each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, fluorine, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy³, andprovided that when n is 1, p is 1, q is 0, A is CHR^(6b), and R¹ ismethyl, then at least two of R⁴, R^(5a), R^(5b), R^(5c), and R^(5d) arenot hydrogen, or a pharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy),—(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), and R^(5d) is independently hydrogen, halogen, —NH₂,—CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R^(5c) is hydrogen,halogen, —CN, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), orCHR^(6b); wherein R^(6a) is hydrogen or C1-C4 alkyl; wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; and wherein R⁷ is hydrogen,halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; providedthat when R^(5b) is morpholinyl and R¹ is thiophenyl or thiazolyl, thenq is 1 and at least one of R^(5a), R^(5c), and R^(5d) is not hydrogen;provided that when q is 0 then Cy¹ is not aryl; and provided that atleast one of R^(5a), R^(5b), R^(5c), and R^(5d) is not hydrogen, or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by a formulaselected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Further disclosed are methods for treating a disorder associated withelevated TXNIP or elevated glucagon in a mammal, comprisingadministering to the mammal a therapeutically effective amount of atleast one pharmaceutical composition or compound as described herein.Also disclosed are methods of lowering hepatic glucose production in amammal in need thereof, comprising administering to the mammal atherapeutically effective amount of at least one pharmaceuticalcomposition or compound as described herein.

Also provided are compositions and methods for use in the prevention andtreatment of hyperlipidemia and/or fatty liver disease (e.g.,nonalcoholic fatty liver disease) in a mammal, optionally in the absenceof elevated TXNIP or in the absence of diabetes or diabetes relateddisorders. The disclosed methods include administering to the mammal atherapeutically effective amount of at least one pharmaceuticalcomposition or compound as described herein.

Also disclosed are methods of identifying an inhibitor ofglucose-induced TXNIP expression comprising culturing cells stablytransfected with an exogenous TXNIP promoter in a first culture mediumcontaining a low level of glucose; culturing a first subset of the cellsof step (a) in a second culture medium containing a high level ofglucose; culturing a second subset of the cells of step (a) in a thirdculture medium containing a high level of glucose and an agent to betested; and comparing the level of TXNIP promoter activity in the firstsubset of cells with the level of TXNIP expression in the second subsetof cells, wherein a lower level of TXNIP promoter activity in the secondsubset of cells as compared to the first subset of cells indicates theagent is an inhibitor of glucose-induced TXNIP expression. Optionally,the method can further comprise determining the identified inhibitor ofglucose-induced TXNIP expression is a selective inhibitor of TXNIPexpression and not a general transcriptional inhibitor comprisingcontacting a cell comprising a first and second exogenous promoter withthe identified inhibitor of glucose-induced TXNIP expression, whereinthe first exogenous promoter is a TXNIP promoter and the secondexogenous promoter promotes expression of a non-TXNIP gene; anddetecting the level of promoter activity of the TXNIP and the non-TXNIPgene, wherein detecting a reduction in the level of TXNIPpromoter-driven gene expression without reduction in the level ofnon-TXNIP promoter-driven gene expression as compared to a control cellwithout contact with the inhibitor of glucose-induced TXNIP determinesthat the identified inhibitor of glucose-induced TXNIP expression is nota general inhibitor of transcription.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of compound #11 (Table 1) on inhibition of TXNIPexpression in primary human pancreatic islets under high glucoseconditions, as compared to control (DMSO treated) islets.

FIG. 2 shows that compound #11 inhibits Type 1 diabetes associatedinflammatory cytokine-induced β-cell death in primary cultures of humanislets.

FIG. 3 shows the results of oral administration of compound #11a (day5-15) in two different models of diabetes. The upper left panel showssignificantly lower blood glucose levels in compound-treated wild-typemice previously treated with multiple low-dose streptozotocin (STZ) (day1-5) to induce diabetes as compared to STZ-treated wild-type mice thatdid not receive compound #11a. The upper right panel shows nodetrimental effect of compound #11a on the body weight of the STZtreated mice as compared to control STZ treated mice. The lower leftpanel shows significantly lower blood glucose levels in obese diabeticdb/db mice (as a model of Type 2 diabetes) treated with compound #11a ascompared to untreated db/db mice. Similar to the STZ treated mice,compound #11a had no significant effect on body weight of the db/db miceas shown in the lower right panel.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated+10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, “IC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half maximal (50%) inhibitoryconcentration (IC) of a substance.

As used herein, “EC₅₀,” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage forms can comprise inventive a disclosed compound, aproduct of a disclosed method of making, or a salt, solvate, orpolymorph thereof, in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, terms such as “elevated,” “increased,” “reduced,” anddecreased” are generally considered relative to a control or normalstate. For example, “a disorder associated with elevated TXNIP” refersto a disease or condition marked by an increase as compared to thenormal or non-diseased state. However, when terms such as “reduce” or“decrease” are used herein relative to treatment, in which they refer tonormalizing the level or amount toward the control or normal state andmay include a partial or complete normalization.

A disorder associated with elevated TXNIP and/or glucagon includes, forexample, “diabetes and associated disorders” (e.g., Type 1 diabetes,Type 2 diabetes, gestational diabetes, impaired glucose tolerance orpre-diabetes, insulin resistance, hyperlipidemia, non-alcoholic fattyliver disease, complications of diabetes, including diabetes-relatednephropathy, neuropathy, retinopathy, cardiomyopathy, and cardiovasculardisease as well as pancreatic p-cell loss or pancreatic isletdysfunction, including dysregulation of insulin and/or glucagonproduction or secretion) or other disorders associated with endoplasmicreticulum stress and/or oxidative stress of the cell (includingendogenous, ex vivo, or transplanted pancreatic islets). As used herein,hyperlipidemia and fatty liver disease, for example, may or may not beassociated with diabetes or elevated TXNIP.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14^(th) edition), thePhysicians' Desk Reference (64^(th) edition), and The PharmacologicalBasis of Therapeutics (12^(th) edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations, anorexics, anti-inflammatoryagents, anti-epileptics, local and general anesthetics, hypnotics,sedatives, antipsychotic agents, neuroleptic agents, antidepressants,anxiolytics, antagonists, neuron blocking agents, anticholinergic andcholinomimetic agents, antimuscarinic and muscarinic agents,antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, andnutrients, antiarthritics, antiasthmatic agents, anticonvulsants,antihistamines, antinauseants, antineoplastics, antipruritics,antipyretics; antispasmodics, cardiovascular preparations (includingcalcium channel blockers, beta-blockers, beta-agonists andantiarrythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula (CH₂)_(a)—, where “a” is an integer of from 2to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA-OA² or—OA¹-(OA²)_(a)-OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and“polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine,including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula S(O)₂A′, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o); —(CH₂)₀₋₄C(O)NR^(o)₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —(CH₂)₀₋₄OC(O)NR^(o) ₂;—C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C1-4 straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•)3, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(•) include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C1-4 aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Greene'sProtective Groups in Organic Synthesis,” P. G. M. Wuts, Wiley, 2014).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5,6,7,8-tetrahydro-2-naphthyl radical.In some embodiments, an organic radical can contain 1-10 inorganicheteroatoms bound thereto or therein, including halogens, oxygen,sulfur, nitrogen, phosphorus, and the like. Examples of organic radicalsinclude but are not limited to an alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, mono-substituted amino, di-substituted amino,acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substitutedalkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide,alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy,substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl,heteroaryl, heterocyclic, or substituted heterocyclic radicals, whereinthe terms are defined elsewhere herein. A few non-limiting examples oforganic radicals that include heteroatoms include alkoxy radicals,trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals andthe like.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and l or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

When the disclosed compounds contain one chiral center, the compoundsexist in two enantiomeric forms. Unless specifically stated to thecontrary, a disclosed compound includes both enantiomers and mixtures ofenantiomers, such as the specific 50:50 mixture referred to as a racemicmixture. The enantiomers can be resolved by methods known to thoseskilled in the art, such as formation of diastereoisomeric salts whichmay be separated, for example, by crystallization (see, CRC Handbook ofOptical Resolutions via Diastereomeric Salt Formation by David Kozma(CRC Press, 2001)); formation of diastereoisomeric derivatives orcomplexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step can liberate the desired enantiomeric form. Alternatively,specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designatedenantiomeric form of the compounds can be provided in enantiomericexcess (e.e.). Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%, for example, greater than60%, greater than 70%, greater than 75%, greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 98%, or greaterthan 99%. In one aspect, the designated enantiomer is substantially freefrom the other enantiomer. For example, the “R” forms of the compoundscan be substantially free from the “S” forms of the compounds and are,thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms ofthe compounds can be substantially free of “R” forms of the compoundsand are, thus, in enantiomeric excess of the “R” forms.

When a disclosed compound has two or more chiral carbons, it can havemore than two optical isomers and can exist in diastereoisomeric forms.For example, when there are two chiral carbons, the compound can have upto four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and(R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirrorimage stereoisomers of one another. The stereoisomers that are notmirror-images (e.g., (S,S) and (R,S)) are diastereomers. Thediastereoisomeric pairs can be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. Unless otherwise specifically excluded, a disclosedcompound includes each diastereoisomer of such compounds and mixturesthereof.

The compounds according to this disclosure may form prodrugs at hydroxylor amino functionalities using alkoxy, amino acids, etc., groups as theprodrug forming moieties. For instance, the hydroxymethyl position mayform mono-, di- or triphosphates and again these phosphates can formprodrugs. Preparations of such prodrug derivatives are discussed invarious literature sources (examples are: Alexander et al., J. Med.Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).The nitrogen function converted in preparing these derivatives is one(or more) of the nitrogen atoms of a compound of the disclosure.

“Derivatives” of the compounds disclosed herein are pharmaceuticallyacceptable salts, prodrugs, deuterated forms, radio-actively labeledforms, isomers, solvates and combinations thereof. The “combinations”mentioned in this context are refer to derivatives falling within atleast two of the groups: pharmaceutically acceptable salts, prodrugs,deuterated forms, radio-actively labeled forms, isomers, and solvates.Examples of radio-actively labeled forms include compounds labeled withtritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and thelike.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Strem Chemicals (Newburyport, Mass.),Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40(John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (JohnWiley and Sons, 4th Edition); and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Methods of Treating or Preventing a Disorder Associated with ElevatedTXNIP or Glucagon

In various aspects, the compounds and compositions disclosed herein areuseful for treating, preventing, ameliorating, controlling or reducingthe risk of a variety of disorders associated with elevated TXNIPexpression and/or elevated glucagon levels, including, for example,diabetes or diabetes related disorders. Thus, in one aspect, disclosedare methods of treating or preventing a disorder associated withelevated TXNIP in a subject, the method comprising the step ofadministering to the subject an effective amount of at least onedisclosed compound or a pharmaceutically acceptable salt thereof.Without meaning to be limited by theory, an effective amount of the atleast one compound or pharmaceutically acceptable salt thereof may workby one or more mechanisms, for example, by directly or indirectlyinhibiting TXNIP expression and signaling and/or by reducing circulatingglucagon levels. Optionally, the compounds or compositions as disclosedherein do not block calcium channels. The clinical outcome optionallyincludes improved blood glucose control, lower hepatic glucoseproduction, lower serum glucagon levels, and/or signs of higher insulinproduction as compared to the absence of at least one compound orpharmaceutically acceptable salt thereof.

In one aspect, disclosed are methods for treating or preventing adisorder associated with elevated TXNIP or elevated glucagon levels in amammal, the method comprising the step of administering to the mammal atherapeutically effective amount of at least one compound having astructure represented by a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy¹; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed are methods for treating or preventing a disorderassociated with elevated TXNIP and/or glucagon in a mammal, the methodcomprising the step of administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula:

wherein n is 0, 1, or 2; wherein each of p and q is independently 0 or1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹; wherein Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy²; wherein Cy², when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4)dialkylamino; wherein R⁷ is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4haloalkyl, or C1-C4 alkoxy; wherein R⁸ is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

In a further aspect, the disorder associated with elevated TXNIP and/orglucagon is a disorder affecting regulation of hepatic glucoseproduction. In a still further aspect, the disorder associated withelevated TXNIP and/or glucagon is diabetes or a diabetes relateddisorder. In yet a further aspect, the diabetes is selected from Type Idiabetes, Type II diabetes, and gestational diabetes. In an even furtheraspect, the diabetes is Type I diabetes. In a still further aspect, thediabetes is Type II diabetes. In yet a further aspect, the diabetes isgestational diabetes.

In various aspects, the disclosed compounds can be used in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of disorders associated with elevatedTXNIP and/or elevated glucagon levels for which disclosed compounds orthe other drugs can have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) can be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and adisclosed compound is preferred. However, the combination therapy canalso include therapies in which a disclosed compound and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the disclosed compounds and the other activeingredients can be used in lower doses than when each is used singly.Accordingly, the pharmaceutical compositions include those that containone or more other active ingredients, in addition to a compound of thepresent invention.

In a further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels. In a furtheraspect, the compound exhibits inhibition of TXNIP expression or functionand/or lowers glucagon levels with an IC₅₀ of from about 0.001 μM toabout 25 μM. In a still further aspect, the compound exhibits inhibitionof TXNIP expression or function and/or lowers glucagon levels with anIC₅₀ of from about 0.001 μM to about 15 μM. In yet a further aspect, thecompound exhibits inhibition of TXNIP expression or function and/orlowers glucagon levels with an IC₅₀ of from about 0.001 μM to about 10μM. In an even further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon with an IC₅₀ of from about0.001 μM to about 5 μM. In a still further aspect, the compound exhibitsinhibition of TXNIP expression or function and/or lowers glucagon levelswith an IC₅₀ of from about 0.001 μM to about 1 μM. In yet a furtheraspect, the compound exhibits inhibition of TXNIP expression or functionand/or lowers glucagon with an IC₅₀ of from about 0.001 μM to about 0.5μM. In an even further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon with an IC₅₀ of from about0.001 μM to about 0.1 μM. In a still further aspect, the compoundexhibits inhibition of TXNIP expression or function and/or lowersglucagon levels with an IC₅₀ of from about 0.001 μM to about 0.05 μM. Inyet a further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels with an IC₅₀ offrom about 0.001 μM to about 0.01 μM. In an even further aspect, thecompound exhibits inhibition of TXNIP expression or function and/orlowers glucagon levels with an IC₅₀ of from about 0.001 μM to about0.005 μM. In a still further aspect, the compound exhibits inhibition ofTXNIP expression or function and/or lowers glucagon levels with an IC₅₀of from about 0.005 μM to about 25 μM. In yet a further aspect, thecompound exhibits inhibition of TXNIP expression or function and/orlowers glucagon levels with an IC₅₀ of from about 0.01 μM to about 25μM. In an even further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels with an IC₅₀ offrom about 0.05 μM to about 25 μM. In a still further aspect, thecompound exhibits inhibition of TXNIP expression or function and/orlowers glucagon levels with a IC₅₀ of from about 0.1 μM to about 25 μM.In yet a further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels with an IC₅₀ offrom about 0.5 μM to about 25 μM. In an even further aspect, thecompound exhibits inhibition of TXNIP expression or function and/orlowers glucagon levels with an IC₅₀ of from about 1 μM to about 25 μM.In a still further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels with an IC₅₀ offrom about 5 μM to about 25 μM. In yet a further aspect, the compoundexhibits inhibition of TXNIP expression or function and/or lowersglucagon levels with an IC₅₀ of from about 10 μM to about 25 μM. In aneven further aspect, the compound exhibits inhibition of TXNIPexpression or function and/or lowers glucagon levels with a IC₅₀ of fromabout 15 μM to about 25 μM.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is a human.

In a further aspect, the subject has been diagnosed with a need fortreatment of the disorder associated with elevated TXNIP and/or glucagonprior to the administering step. In a still further aspect, the subjectis at risk for developing the disorder prior to the administering step.

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the method further comprises identifying a subjectat risk for developing the disorder prior to the administering step.

In a further aspect, the method further comprises the step ofidentifying a subject in need of treatment of a disorder associated withelevated TXNIP and/or glucagon.

C. Methods of Treating or Preventing Hyperlipedmia or Fatty LiverDisease

Described herein are methods for preventing or treating hyperlipidemiaand/or fatty liver disease (e.g., nonalcoholic fatty liver disease) in asubject. The methods comprise administering to the subject an effectiveamount of at least one disclosed compound, or a pharmaceuticallyacceptable salt thereof. The hyperlipidemia and/or fatty liver diseaseis optionally in the presence or absence of elevated TXNIP or in thepresence or absence of diabetes or other diabetes related disorders.Without meaning to be limited by theory, the disclosed compounds orpharmaceutical salts are effective in treating hyperlipidemia or fattyliver disease even without an apparent need for reduction of TXNIP. Thedisclosed methods include administering to the mammal a therapeuticallyeffective amount of at least one pharmaceutical composition or compoundas described herein.

The disclosed compounds can be used in combination with one or moreother drugs in the treatment, prevention, control, amelioration, orreduction of risk of hyperlipidemia and/or fatty liver disease, wherethe combination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) can be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a disclosed compound, as described above.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is a human.

In a further aspect, the subject has been diagnosed with a need fortreatment of hyperlipidemia and/or fatty liver disease prior to theadministering step. In a still further aspect, the subject is at riskfor developing hyperlipidemia and/or fatty liver disease prior to theadministering step.

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the method further comprises identifying a subjectat risk for developing hyperlipidemia and/or fatty liver disease priorto the administering step.

D. Methods of Inhibiting TXNIP Expression or Function or LoweringHepatic Glucose Production in a Subject

In various aspects, disclosed are methods of inhibiting TXNIP expressionor function or lowering hepatic glucose production in a subject, themethod comprising the step of administering to the subject an effectiveamount of at least one disclosed compound, or a pharmaceuticallyacceptable salt thereof. The method of inhibiting TXNIP expression orfunction or lowering hepatic glucose production (e.g., by reducingglucagon levels) is optionally selected from the group consisting ofdiabetes, diabetes related disorders, hyperlipidemia, and fatty liverdisease.

In one aspect, disclosed are methods for inhibiting TXNIP expression orfunction and/or lowering hepatic glucose production in a mammal, themethod comprising the step of administering to the mammal an effectiveamount of at least one compound having a structure represented by aformula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —N₁₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed are methods for inhibiting TXNIP expression and/orlowering hepatic glucose production in a mammal, the method comprisingthe step of administering to the mammal an effective amount of at leastone compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of p and q is independently 0 or1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹; wherein Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy²; wherein Cy², when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4)dialkylamino; wherein R⁷ is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4haloalkyl, or C1-C4 alkoxy; wherein R⁸ is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

In a further aspect, inhibiting TXNIP expression and/or lowering hepaticglucose production in the mammal treats diabetes in the mammal.

In a further aspect, the subject has been diagnosed with a disorderassociated with elevated TXNIP and/or glucagon prior to theadministering step. In a still further aspect, the subject has beendiagnosed with diabetes prior to the administering step. In yet afurther aspect, the method further comprises the step of identifying asubject in need of treatment of a disorder of hepatic glucose regulationdysfunction. In an even further aspect, the method further comprises thestep of identifying a subject in need of treatment of diabetes.

In a further aspect, the subject has been diagnosed with a need forinhibition of TXNIP and/or lowering hepatic glucose production prior tothe administering step. In a still further aspect, the subject has beendiagnosed with a need for treatment of a disorder associated withelevated TXNIP and/or glucagon prior to the administering step. In yet afurther aspect, the method further comprises the step of identifying asubject in need of treatment.

In a further aspect, the disorder associated with elevated TXNIP and/orglucagon is a disorder of hepatic glucose regulation dysfunction. In astill further aspect, the disorder is diabetes. In yet a further aspect,the diabetes is selected from Type I diabetes, Type II diabetes,gestational diabetes, or pre-diabetes/impaired glucose tolerance or adiabetes related disorder. In an even further aspect, the diabetes isType I diabetes. In a still further aspect, the diabetes is Type IIdiabetes. In yet a further aspect, the diabetes is gestational diabetesor pre-diabetes/impaired glucose tolerance.

In a further aspect, the compound exhibits inhibition of TXNIP and/orlowers glucagon levels with an IC₅₀ of from about 0.001 μM to about 25μM. In a still further aspect, the compound exhibits inhibition of TXNIPand/or lowers glucagon with an IC₅₀ of from about 0.001 μM to about 15μM. In yet a further aspect, the compound exhibits inhibition of TXNIPand/or lowers glucagon levels with an IC₅₀ of from about 0.001 μM toabout 10 μM. In an even further aspect, the compound exhibits inhibitionof TXNIP and/or lowers glucagon levels with an IC₅₀ of from about 0.001μM to about 5 μM. In a still further aspect, the compound exhibitsinhibition of TXNIP and/or lowers glucagon levels with an IC₅₀ of fromabout 0.001 μM to about 1 μM. In yet a further aspect, the compoundexhibits inhibition of TXNIP and/or lowers glucagon levels with an IC₅₀of from about 0.001 μM to about 0.5 μM. In an even further aspect, thecompound exhibits inhibition of TXNIP and/or lowers glucagon levels withan IC₅₀ of from about 0.001 μM to about 0.1 μM. In a still furtheraspect, the compound exhibits inhibition of TXNIP and/or lowers glucagonlevels with an IC₅₀ of from about 0.001 μM to about 0.05 μM. In yet afurther aspect, the compound exhibits inhibition of TXNIP and/or lowersglucagon levels with an IC₅₀ of from about 0.001 μM to about 0.01 μM. Inan even further aspect, the compound exhibits inhibition of TXNIP and/orlowers glucagon levels with an IC₅₀ of from about 0.001 μM to about0.005 μM. In a still further aspect, the compound exhibits inhibition ofTXNIP and/or lowers glucagon levels with an IC₅₀ of from about 0.005 μMto about 25 μM. In yet a further aspect, the compound exhibitsinhibition of TXNIP and/or lowers glucagon levels with an IC₅₀ of fromabout 0.01 μM to about 25 μM. In an even further aspect, the compoundexhibits inhibition of TXNIP and/or lowers glucagon levels with an IC₅₀of from about 0.05 μM to about 25 μM. In a still further aspect, thecompound exhibits inhibition of TXNIP and/or lowers glucagon levels withan IC₅₀ of from about 0.1 μM to about 25 μM. In yet a further aspect,the compound exhibits inhibition of TXNIP and/or lowers glucagon levelswith an IC₅₀ of from about 0.5 μM to about 25 μM. In an even furtheraspect, the compound exhibits inhibition of TXNIP and/or lowers glucagonlevels with an IC₅₀ of from about 1 μM to about 25 μM. In a stillfurther aspect, the compound exhibits inhibition of TXNIP and/or lowersglucagon levels with an IC₅₀ of from about 5 μM to about 25 μM. In yet afurther aspect, the compound exhibits inhibition of TXNIP and/or lowersglucagon levels with an IC₅₀ of from about 10 μM to about 25 μM. In aneven further aspect, the compound exhibits inhibition of TXNIP and/orlowers glucagon levels with an IC₅₀ of from about 15 μM to about 25 μM.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is a human.

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

E. Methods of Identifying an Inhibitor of Glucose-Induced TXNIPExpression

Provided herein is a method of identifying an inhibitor ofglucose-induced TXNIP expression. The method includes culturing cellsstably transfected with an exogenous TXNIP promoter (e.g., a human TXNIPpromoter) in a first culture medium containing a low level of glucose;then culturing a first subset of the cells in a second culture mediumcontaining a high level of glucose and a second subset of the cells in athird culture medium containing a high level of glucose and an agent tobe tested; and comparing the level of TXNIP promoter activity in thefirst subset of cells with the level of TXNIP promoter activity in thesecond subset of cells. A lower level of TXNIP promoter activity in thesecond subset of cells as compared to the first subset of cellsindicates the agent is an inhibitor of glucose-induced TXNIP expression.

In the method of identifying an inhibitor of glucose-induced TXNIPexpression, culturing in a high level of glucose or a low level ofglucose refers to the levels higher or lower than the optimal level ofglucose for culture of the specific cell type. For example, the optimalglucose level for culturing INS-1 cells is about 11.1 mM. Thus a lowlevel of glucose is less than 11.1 (e.g., 3-10 mM, 5-7 mM, or morespecifically about 5 mM), and a high level of glucose is higher than11.1 (e.g., 12-30 mM, 15-25 mM, or, more specifically, about 25 mM).

Optionally, the method further includes determining the identifiedinhibitor of glucose-induced TXNIP expression is a selective inhibitorof TXNIP expression rather than a general transcriptional inhibitor bytesting its effects on the promoter of a non-TXNIP gene (e.g., a CMVpromoter) and/or treating a cell co-transfected with a first and secondexogenous promoter with the identified inhibitor of glucose-inducedTXNIP expression, wherein the first exogenous promoter is a TXNIPpromoter and the second exogenous promoter promotes expression of acontrol non-TXNIP gene (e.g., a pRLTK promoter), and detecting the levelof promoter activity of the TXNIP and the non-TXNIP gene. Detecting areduction in the level of the TXNIP promoter activity without reductionin the level of the non-TXNIP gene control promoter as compared to acontrol cell without contact with the inhibitor of glucose-induced TXNIPdetermines that the identified inhibitor of glucose-induced TXNIPexpression is not a general transcriptional inhibitor.

Optionally, the method further comprises screening the inhibitor ofglucose-induced TXNIP by contacting a primary culture of cells (e.g.,isolated islets or cardiomyocytes) with the agent in the presence of lowand high glucose and/or by administering the inhibitor to a subject withdiabetes.

F. Pharmaceutical Compositions

In one aspect, disclosed are pharmaceutical compositions comprising adisclosed compound, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or1; wherein R¹ is —N₁₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹,when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, andis substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen, —OH, C1-C4alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein each occurrence ofR^(8a) and R^(8b), when present, is independently hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein p is 1 and each of R^(8a)and R^(8b) together comprise ═O; and wherein R⁹ is hydrogen, C1-C4alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino, or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy),—(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), and R^(5d) is independently hydrogen, halogen, —NH₂,—CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R^(5c) is hydrogen,halogen, —NH₂, —OH, —CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), orCHR^(6b); wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b)is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ ishydrogen, halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy;provided that when R^(5b) is morpholinyl and R¹ is thiophenyl orthiazolyl, then q is 1 and at least one of R^(5a), R^(5c), and R^(5d) isnot hydrogen, or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

Also disclosed are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy²; wherein Cy², when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(5a), R^(5b), R^(5b), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4)dialkylamino; wherein R⁷ is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4haloalkyl, or C1-C4 alkoxy; wherein R⁸ is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed are pharmaceutical compositions comprisingpharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy²; wherein Cy², when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; and R^(5c) is hydrogen, halogen, —CN, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), orCHR^(6b); wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b)is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, or (C1-C4)(C1-C4) dialkylamino; wherein R⁷ is hydrogen,halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy, or apharmaceutically acceptable salt thereof.

In various aspects, the compounds and compositions of the invention canbe administered in pharmaceutical compositions, which are formulatedaccording to the intended method of administration. The compounds andcompositions described herein can be formulated in a conventional mannerusing one or more physiologically acceptable carriers or excipients. Forexample, a pharmaceutical composition can be formulated for local orsystemic administration, e.g., administration by drops or injection intothe ear, insufflation (such as into the ear), intravenous, topical, ororal administration.

The nature of the pharmaceutical compositions for administration isdependent on the mode of administration and can readily be determined byone of ordinary skill in the art. In various aspects, the pharmaceuticalcomposition is sterile or sterilizable. The therapeutic compositionsfeatured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used includebuffers (for example, citrate buffer, phosphate buffer, acetate buffer,and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, polypeptides (for example, serum albumin), EDTA, sodiumchloride, liposomes, mannitol, sorbitol, water, and glycerol. Thenucleic acids, polypeptides, small molecules, and other modulatorycompounds featured in the invention can be administered by any standardroute of administration. For example, administration can be parenteral,intravenous, subcutaneous, or oral. A modulatory compound can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made foradministration by drops into the ear, for injection, or for ingestion;gels or powders can be made for ingestion or topical application.Methods for making such formulations are well known and can be found in,for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro,ed., Mack Publishing Co., Easton, Pa. 1990.

In various aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In various aspects, the pharmaceutical compositions of this inventioncan include a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of the compounds of the invention. Thecompounds of the invention, or pharmaceutically acceptable saltsthereof, can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an evenfurther aspect, the human is a patient.

In a further aspect, the pharmaceutical composition is used to treat adisorder associated with TXNIP activity such as, for example, a disorderassociated with elevated TXNIP (e.g., diabetes).

In a further aspect, the pharmaceutical composition is used to treat adisorder of hepatic glucose regulation dysfunction. In a still furtheraspect, the disorder associated with elevated TXNIP is diabetes. In yeta further aspect, the diabetes is Type I diabetes, Type II diabetes, orgestational diabetes. In an even further aspect, the diabetes is Type Idiabetes. In a still further aspect, the diabetes is Type II diabetes.In yet a further aspect, the diabetes is gestational diabetes.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

G. COMPOUNDS

In one aspect, disclosed are compounds useful in treating or preventinga disorder associated with TXNIP activity such as, for example,disorders associated with elevated TXNIP and/or elevated glucagon levels(e.g., diabetes). In a further aspect, the disclosed compounds exhibitmodulation of TXNIP activity. In a still further aspect, the disclosedcompounds exhibit inhibition of TXNIP activity.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compound having a structure represented bya formula:

wherein n is 0, 1, or 2; wherein p is 1, 2, 3, or 4; wherein q is 0 or1; wherein R¹ is —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen, —OH, C1-C4alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; and wherein each occurrence ofR^(8a) and R^(8b), when present, is independently hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein p is 1 and each of R^(8a)and R^(8b) together comprise ═O; provided that when R¹ is methyl andeach of R³ and R⁴ is hydrogen then each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, fluorine, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy³, andprovided that when n is 1, p is 1, q is 0, A is CHR^(6b), and R¹ ismethyl, then at least two of R⁴, R^(5a), R^(5b), R^(5c), and R^(5d) arenot hydrogen, or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed are compounds having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; and wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O.

In a further aspect, disclosed are compounds having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.

In a further aspect, disclosed are compounds having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy¹; wherein Cy¹, when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R² are covalently bonded together and, together with theintermediate atoms, comprise a 3- to 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ is hydrogen or C1-C4alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²; whereinCy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a),R^(5b), R^(5c), and R^(5d) is independently hydrogen, halogen, —NH₂,—CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,or (C1-C4)(C1-C4) dialkylamino; wherein R⁷ is hydrogen, halogen, —OH,C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; and wherein R⁸ ishydrogen, C1-C4 alkyl, or C1-C4 haloalkyl; with the proviso that when R¹is methyl and each of R³ and R⁴ is hydrogen then each of R^(5a), R^(5b),R^(5c), and R^(5d) is independently hydrogen, fluorine, —NH₂, —OH, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, orCy³, or a pharmaceutically acceptable salt thereof.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0, 1, or 2; wherein q is 0 or 1; wherein R¹ is —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy),—(C1-C4 alkyl)CO₂H, or Cy¹; wherein Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen or C1-C4 alkyl, orwherein each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R³ are covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 7-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy²;wherein Cy², when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein eachof R^(5a), R^(5b), and R^(5d) is independently hydrogen, halogen, —NH₂,—CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R^(5c) is hydrogen,halogen, —CN, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 haloalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), orCHR^(6b); wherein R^(6a) is hydrogen or C1-C4 alkyl; wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; and wherein R⁷ is hydrogen,halogen, —OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; providedthat when R^(5b) is morpholinyl and R¹ is thiophenyl or thiazolyl, thenq is 1 and at least one of R^(5a), R^(5c), and R^(5d) is not hydrogen;provided that when q is 0 then Cy¹ is not aryl; and provided that atleast one of R^(5a), R^(5b), R^(5c), and R^(5d) is not hydrogen, or apharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound is not:

In a further aspect, the compound is not:

In a further aspect, the compound is not:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, p is 0 or 1; R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,or Cy¹; each of R^(5a), R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; andR^(8a) is hydrogen and R^(8b) is hydrogen, C1-C4 alkyl, or C1-C4haloalkyl.

In a further aspect, p is 1; R¹ is —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹;each of R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; and R^(8a) ishydrogen and R^(8b) is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

In a further aspect, R¹ is methyl and each of R³ and R⁴ is hydrogen theneach of R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,fluorine, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy³. In a still further aspect, R¹ ismethyl, each of R³ and R⁴ is hydrogen, and each of R^(5a), R^(5b),R^(5c), and R^(5d) is independently hydrogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy³. Inyet a further aspect, R¹ is methyl, each of R³ and R⁴ is hydrogen, andR^(8b) is fluorine.

In one aspect, n is 0, 1, or 2. In a further aspect, n is 0 or 1. In astill further aspect, n is 1 or 2. In yet a further aspect, n is 0. Inan even further aspect, n is 1. In a still further aspect, n is 2.

In a further aspect, q is 0 or 1. In a still further aspect, q is 0. Inyet a further aspect, q is 1.

In one aspect, p is 0, 1, 2, 3, or 4. In a further aspect, p is 1, 2, 3,or 4. In a further aspect, p is 0 or 1. In a still further aspect, p is0. In yet a further aspect, p is 1.

In a further aspect, each of p and q is independently 0 or 1. In a stillfurther aspect, p is 0 and q is 1. In yet a further aspect, p is 1 and qis 0. In an even further aspect, p is 0 or 1 and q is 0. In a stillfurther aspect, q is 0 or 1 and p is 0. In yet a further aspect, p is 0or 1 and q is 1. In an even further aspect, q is 0 or 1 and p is 1. In astill further aspect, each of p and q is 0. In yet a further aspect,each of p and q is 1.

a. A Groups

In one aspect, A is O, NR^(6a), or CHR^(6b). In a further aspect, A is Oor NR^(6a). In a still further aspect, A is O or CHR^(6b). In yet afurther aspect, A is NR^(6a) or CHR^(6b). In an even further aspect, Ais O. In a still further aspect, A is NR^(6a). In yet a further aspect,A is CHR^(6b). In an even further aspect, A is NH. In a still furtheraspect, A is CH₂.

b. R¹ Groups

In one aspect, R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹.

In one aspect, each of R¹ and R³ are covalently bonded together and,together with the intermediate atoms, comprise a 5- to 7-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a furtheraspect, each of R¹ and R³ are covalently bonded together and, togetherwith the intermediate atoms, comprise a 5- to 7-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, each of R¹ and R³ are covalently bonded together and,together with the intermediate atoms, comprise a 5- to 7-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each of R¹ andR³ are covalently bonded together and, together with the intermediateatoms, comprise a 5- to 7-membered heterocycloalkyl monosubstituted witha group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, each of R¹ and R³ are covalently bonded togetherand, together with the intermediate atoms, comprise an unsubstituted 5-to 7-membered heterocycloalkyl.

In one aspect, R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹.

In one aspect, R¹ is —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹.

In a further aspect, R¹ is —NH₂, —OH, methyl, ethyl, n-propyl, i-propyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—CH₂CO₂H, —CH₂CH₂CO₂H, —CH₂CH₂CH₂CO₂H, or Cy¹. In a still furtheraspect, R¹ is —NH₂, —OH, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —CH₂OH, —CH₂CH₂OH, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CO₂H,—CH₂CH₂CO₂H, or Cy¹. In yet a further aspect, R¹ is —NH₂, —OH, methyl,—CH₂F, —CH₂Cl, —OCH₃, —CH₂OH, —NHCH₃, —N(CH₃)₂, —CH₂OCH₃, —CH₂CO₂H, orCy¹.

In a further aspect, R¹ is —NH₂, —OH, methyl, ethyl, n-propyl, i-propyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy¹. In a stillfurther aspect, R¹ is —NH₂, —OH, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In yet a further aspect, R¹ is —NH₂, —OH,methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy¹.

In a further aspect, R¹ is —OH, methyl, ethyl, n-propyl, i-propyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy¹. In a stillfurther aspect, R¹ is —OH, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In yet a further aspect, R¹ is —OH, methyl,—CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy¹.

In a further aspect, R¹ is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, or Cy¹. In a stillfurther aspect, R¹ is methyl, ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy¹. In yet afurther aspect, R¹ is methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In an even further aspect, R¹ is methyl, —CH₂F,—CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy¹.

In a further aspect, R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹. In a still furtheraspect, R¹ is —NH₂, —OH, methyl, ethyl, n-propyl, i-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In a still further aspect, R¹ is —NH₂, —OH,methyl, ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy¹. In yet a further aspect, R¹ is—NH₂, —OH, methyl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy¹.

In a further aspect, R¹ is —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹. In a still furtheraspect, R¹ is —OH, methyl, ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In a still further aspect, R¹ is —OH, methyl,ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy¹. In yet a further aspect, R¹ is —OH, methyl,—OCH₃, —NHCH₃, —N(CH₃)₂, or Cy¹.

In a further aspect, R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, or Cy¹.In a still further aspect, R¹ is —NH₂, —OH, methyl, ethyl, n-propyl,i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, or Cy¹. In a stillfurther aspect, R¹ is —NH₂, —OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, or Cy¹.In yet a further aspect, R¹ is —NH₂, —OH, methyl, —OCH₃, or Cy¹.

In a further aspect, R¹ is —OH, C1-C4 alkyl, C1-C4 alkoxy, or Cy¹. In astill further aspect, R¹ is —OH, methyl, ethyl, n-propyl, i-propyl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, or Cy¹. In a still furtheraspect, R¹ is —OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, or Cy¹. In yet afurther aspect, R¹ is —OH, methyl, —OCH₃, or Cy¹.

In a further aspect, R¹ is C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4alkoxy. In a still further aspect, R¹ is methyl, ethyl, n-propyl,i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or—OCH(CH₃)CH₃. In yet a further aspect, R¹ is methyl, ethyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or —OCH₂CH₃. In yet a furtheraspect, R¹ is methyl, —CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, R¹ is Cy¹.

In a further aspect, R¹ is C1-C4 haloalkyl. In a still further aspect,R¹ is —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In yet a further aspect, R¹ is —CH₂F,—CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl. In yet a further aspect, R¹ is —CH₂F or—CH₂C1.

In a further aspect, R¹ is C1-C4 alkyl. In a still further aspect, R¹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl. In yet a further aspect, R¹ is methyl, ethyl, n-propyl, ori-propyl. In an even further aspect, R¹ is methyl or ethyl. In a stillfurther aspect, R¹ is ethyl. In yet a further aspect, R¹ is methyl.

In a further aspect, each of R¹ and R³ are covalently bonded togetherand, together with the intermediate atoms, comprise a 5- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, R¹ and R³ are covalently bonded together and, togetherwith the intermediate atoms, comprise a 5- to 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, R¹ and R³ are covalently bonded together and, togetherwith the intermediate atoms, comprise a 5- to 6-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, R¹ and R³are covalently bonded together and, together with the intermediateatoms, comprise a 5- to 6-membered heterocycloalkyl monosubstituted witha group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, R¹ and R³ are covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted 5- to6-membered heterocycloalkyl.

In a further aspect, each of R¹ and R³ are covalently bonded togetherand, together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, each of R¹ and R³ are covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, each of R¹ and R³ are covalently bonded together and,together with the intermediate atoms, comprise a 7-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

c. R² Groups

In one aspect, R² is hydrogen or C1-C4 alkyl, or wherein each of R¹ andR² are covalently bonded together and, together with the intermediateatoms, comprise a 3- to 6-membered heterocycloalkyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino.

In a further aspect, R² is hydrogen or C1-C4 alkyl. In a still furtheraspect, R² is hydrogen.

In a further aspect, R² is hydrogen, methyl, ethyl, isopropyl, n-propyl,isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R² ishydrogen, methyl, ethyl, isopropyl, or n-propyl. In yet a furtheraspect, R² is hydrogen, methyl, or ethyl. In an even further aspect, R²is hydrogen or methyl. In a still further aspect, R² is hydrogen orethyl.

In a further aspect, R² is methyl, ethyl, isopropyl, n-propyl, isobutyl,n-butyl, s-butyl, or t-butyl. In a still further aspect, R² is methyl,ethyl, isopropyl, or n-propyl. In yet a further aspect, R² is methyl, orethyl. In an even further aspect, R² is methyl. In a still furtheraspect, R² is ethyl.

In a further aspect, each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, each of R¹ and R² are covalently bonded together and,together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In yet a furtheraspect, each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino. In an even further aspect, each of R¹ andR² are covalently bonded together and, together with the intermediateatoms, comprise a 3- to 6-membered heterocycloalkyl monosubstituted witha group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, each of R¹ and R² are covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted 3- to6-membered heterocycloalkyl.

In a further aspect, each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 5-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, each of R¹ and R² are covalently bonded together and,together with the intermediate atoms, comprise a 3- to 4-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In yet a furtheraspect, each of R¹ and R² are covalently bonded together and, togetherwith the intermediate atoms, comprise a 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino. In an even further aspect, eachof R¹ and R² are covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each of R¹ andR² are covalently bonded together and, together with the intermediateatoms, comprise a 4-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a3-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.

d. R³ Groups

In one aspect, R³ is hydrogen or C1-C4 alkyl. In a further aspect, R³ ishydrogen.

In a further aspect, R³ is hydrogen, methyl, ethyl, isopropyl, n-propyl,isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect, R³ ishydrogen, methyl, ethyl, isopropyl, or n-propyl. In yet a furtheraspect, R³ is hydrogen, methyl, or ethyl. In an even further aspect, R³is hydrogen or methyl. In a still further aspect, R³ is hydrogen orethyl.

In a further aspect, R³ is methyl, ethyl, isopropyl, n-propyl, isobutyl,n-butyl, s-butyl, or t-butyl. In a still further aspect, R³ is methyl,ethyl, isopropyl, or n-propyl. In yet a further aspect, R³ is methyl, orethyl. In an even further aspect, R³ is methyl. In a still furtheraspect, R³ is ethyl.

e. R⁴ Groups

In one aspect, R⁴ is hydrogen, halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy². In afurther aspect, R⁴ is hydrogen.

In a further aspect, R⁴ is —F, —Cl, —NH₂, —OH, methyl, ethyl, n-propyl,i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy². In a stillfurther aspect, R⁴ is —F, —Cl, —NH₂, —OH, methyl, ethyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy². In yet a further aspect, R⁴ is —F,—Cl, —NH₂, —OH, methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy².

In a further aspect, R⁴ is C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, or Cy². In a stillfurther aspect, R⁴ is methyl, ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy². In yet afurther aspect, R⁴ is methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), or Cy². In an even further aspect, R⁴ is methyl, —CH₂F,—CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy².

In a further aspect, R⁴ is —F, —Cl, —NH₂, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy². In astill further aspect, R⁴ is —F, —Cl, —NH₂, —OH, methyl, ethyl, n-propyl,i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy². In a still further aspect, R⁴is —F, —Cl, —NH₂, —OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy². In yet afurther aspect, R⁴ is —F, —Cl, —NH₂, —OH, methyl, —OCH₃, —NHCH₃,—N(CH₃)₂, or Cy².

In a further aspect, R⁴ is —F, —Cl, —NH₂, —OH, C1-C4 alkyl, C1-C4alkoxy, or Cy². In a still further aspect, R⁴ is —F, —Cl, —NH₂, —OH,methyl, ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, or Cy². In a still further aspect, R⁴ is —F, —Cl, —NH₂,—OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, or Cy². In yet a further aspect, R⁴is —F, —Cl, —NH₂, —OH, methyl, —OCH₃, or Cy².

In a further aspect, R⁴ is C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4alkoxy. In a still further aspect, R⁴ is methyl, ethyl, n-propyl,i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or—OCH(CH₃)CH₃. In yet a further aspect, R⁴ is methyl, ethyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or —OCH₂CH₃. In yet a furtheraspect, R⁴ is methyl, —CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, R⁴ is Cy².

In a further aspect, R⁴ is C1-C4 haloalkyl. In a still further aspect,R⁴ is —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In yet a further aspect, R⁴ is —CH₂F,—CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl. In yet a further aspect, R⁴ is —CH₂F or—CH₂Cl.

In a further aspect, R⁴ is C1-C4 alkyl. In a still further aspect, R⁴ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl. In yet a further aspect, R⁴ is methyl, ethyl, n-propyl, ori-propyl. In an even further aspect, R⁴ is methyl or ethyl. In a stillfurther aspect, R⁴ is ethyl. In yet a further aspect, R⁴ is methyl.

f. R^(5A), R^(5B), R^(5c), and R^(5D) Groups

In one aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³.

In one aspect, each of R⁵, R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In afurther aspect, at least one of R⁵, R^(5b), R^(5c), and R^(5d) is nothydrogen. In a still further aspect, one of R^(5a), R^(5b), R^(5c), andR^(5d) is hydrogen. In yet a further aspect, two of R^(5a), R^(5b),R^(5c), and R^(5d) is hydrogen. In an even further aspect, three ofR^(5a), R^(5b), R^(5c), and R^(5d) are hydrogen.

In one aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; andR^(5c) is hydrogen, halogen, —CN, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), oraryl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, —OCF₃, —OCH₂CF₃, —OCH₂CH₂CF₃, —OCH(CH₃)CF₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃,—CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —NHC(O)CH(CH₃)₂, or Cy³. In a stillfurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —OCF₃, —OCH₂CF₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃,—CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In yet afurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, —CH₂F, —CH₂Cl,—OCH₃, —OCF₃, —NHCH₃, —N(CH₃)₂, —CO₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃,—CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —NHC(O)CH(CH₃)₂, or Cy³. Ina still further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In yet a furtheraspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃,—N(CH₃)₂, —CO₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl),—CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In a stillfurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, methyl, ethyl, n-propyl, i-propyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃,—CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —NHC(O)CH(CH₃)₂, or Cy³. In yet afurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In an even further aspect, each ofR^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen, methyl,—CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, —CO₂CH₃, —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In astill further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃,—CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —NHC(O)CH(CH₃)₂, or Cy³. In a stillfurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —OCH₃,—OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃),—CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, or Cy³. In yet a further aspect, each of R^(5a), R^(5b),R^(5c), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂, —CN, —OH,methyl, —OCH₃, —NHCH₃, —N(CH₃)₂, —CO₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4alkoxy, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4alkyl), or Cy³. In a still further aspect, each of R^(5a), R^(5b),R^(5c), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂, —CN, —OH,methyl, ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃,—NHC(O)CH(CH₃)₂, or Cy³. In a still further aspect, each of R^(5a),R^(5b), R^(5c), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂,—CN, —OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In yet a furtheraspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, —OCH₃, —CO₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or Cy³. In a still further aspect, eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy.In a still further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, methyl, ethyl, n-propyl, i-propyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)CH₃. In yet afurther aspect, each of R⁵, R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or—OCH₂CH₃. In yet a further aspect, each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, methyl, —CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen or Cy³.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³,or —NHC(O)(C1-C4 alkyl). In a still further aspect, each of R^(5a),R^(5b), R^(5c), and R^(5d) is independently hydrogen, —CO₂CH₃,—CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, or —NHC(O)CH(CH₃)₂. In yeta further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, or —NHC(O)CH₂CH₃. In an even further aspect, each of R^(5a),R^(5b), R^(5c), and R^(5d) is independently hydrogen, —CO₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, or —NHC(O)CH₃.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen or C1-C4 haloalkyl. In a still further aspect,each of R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In yet a further aspect, each of R^(5a),R^(5b), R^(5c), and R^(5d) is independently hydrogen, —CH₂F, —CH₂Cl,—CH₂CH₂F, or —CH₂CH₂C1. In yet a further aspect, each of R^(5a), R^(5b),R^(5c), and R^(5d) is independently hydrogen, —CH₂F or —CH₂C1.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen or C1-C4 alkyl. In a still further aspect, eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yeta further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, methyl, ethyl, n-propyl, or i-propyl. In an evenfurther aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, methyl or ethyl. In a still further aspect, eachof R^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen orethyl. In yet a further aspect, each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen or methyl.

In a further aspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a furtheraspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a further aspect, each ofR^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen, —F, —Cl,—NH₂, —CN, —OH, methyl, ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F,—CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still furtheraspect, each of R^(5a), R^(5b), R^(5c), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃). In yet a further aspect, each ofR^(5a), R^(5b), R^(5c), and R^(5d) is independently hydrogen, —F, —Cl,—NH₂, —CN, —OH, methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, n-propyl, i-propyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy³. In a stillfurther aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —CH₂F, —CH₂Cl,—CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), or Cy³. In yet a further aspect, each ofR^(5a), R^(5b), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂,—CN, —OH, methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, or Cy³.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,or (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In a still further aspect,each of R^(5a), R^(5b), and R^(5d) is independently hydrogen, methyl,ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂,—CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃,—NHC(O)CH(CH₃)₂, or Cy³. In yet a further aspect, each of R^(5a),R^(5b), and R^(5d) is independently hydrogen, methyl, ethyl, —CH₂F,—CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In an evenfurther aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, methyl, —CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, —N(CH₃)₂, —CO₂CH₃,—CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In a still furtheraspect, each of R^(5a), R^(5b), and R^(5d) is independently hydrogen,—F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, n-propyl, i-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,—N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂,—CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃,—NHC(O)CH(CH₃)₂, or Cy³. In a still further aspect, each of R^(5a),R^(5b), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂, —CN, —OH,methyl, ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)CH₃, —NHC(O)CH₂CH₃, or Cy³. In yet a further aspect,each of R^(5a), R^(5b), and R^(5d) is independently hydrogen, —F, —Cl,—NH₂, —CN, —OH, methyl, —OCH₃, —NHCH₃, —N(CH₃)₂, —CO₂CH₃, —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —F, —Cl, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 alkoxy, —CO₂(C1-C4alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³. In astill further aspect, each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —CO₂CH₃,—CO₂CH₂CH₃, —CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,—NHC(O)CH₃, —NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, —NHC(O)CH(CH₃)₂, or Cy³. Ina still further aspect, each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —OCH₃,—OCH₂CH₃, —CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, or Cy³. In yet a further aspect, each of R^(5a), R^(5b),and R^(5d) is independently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl,—OCH₃, —CO₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or Cy³.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy. In a stillfurther aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, methyl, ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)CH₃. In yet a further aspect,each of R^(5a), R^(5b), and R^(5d) is independently hydrogen, methyl,ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or —OCH₂CH₃. In yet afurther aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, methyl, —CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen or Cy³.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, or—NHC(O)(C1-C4 alkyl). In a still further aspect, each of R^(5a), R^(5b),and R^(5d) is independently hydrogen, —CO₂CH₃, —CO₂CH₂CH₃,—CO₂CH₂CH₂CH₃, —CO₂CH(CH₃)₂, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃,—NHC(O)CH₂CH₃, —NHC(O)CH₂CH₂CH₃, or —NHC(O)CH(CH₃)₂. In yet a furtheraspect, each of R^(5a), R⁵, and R^(5d) is independently hydrogen,—CO₂CH₃, —CO₂CH₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)CH₃, or—NHC(O)CH₂CH₃. In an even further aspect, each of R^(5a), R^(5b), andR^(5d) is independently hydrogen, —CO₂CH₃, —CO₂H, —CO₂NH₂, —NHC(O)Cy³,or —NHC(O)CH₃.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen or C1-C4 haloalkyl. In a still further aspect, each of R^(5a),R^(5b), and R^(5d) is independently hydrogen, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. Inyet a further aspect, each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen, —CH₂F, —CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl. In yet afurther aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, —CH₂F or —CH₂C1.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen or C1-C4 alkyl. In a still further aspect, each of R^(5a),R^(5b), and R^(5d) is independently hydrogen, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yet a furtheraspect, each of R^(5a), R^(5b) and R^(5d) is independently hydrogen,methyl, ethyl, n-propyl, or i-propyl. In an even further aspect, each ofR^(5a), R^(5b), and R^(5d) is independently hydrogen, methyl or ethyl.In a still further aspect, each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen or ethyl. In yet a further aspect, each ofR^(5a), R^(5b), and R^(5d) is independently hydrogen or methyl.

In a further aspect, each of R^(5a), R^(5b), and R^(5d) is independentlyhydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a further aspect, each ofR^(5a), R^(5b), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂,—CN, —OH, methyl, ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still further aspect, each ofR^(5a), R^(5b), and R^(5d) is independently hydrogen, —F, —Cl, —NH₂,—CN, —OH, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃,—OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃).In yet a further aspect, each of R^(5a), R^(5b), and R^(5d) isindependently hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, —CH₂F, —CH₂Cl,—OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(5b) is fluorine.

In a further aspect, R^(5c) is hydrogen, halogen, —NH₂, —CN, —OH, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.In a further aspect, R^(5c) is hydrogen, halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.In a still further aspect, R^(5c) is hydrogen, halogen, —NH₂, —OH,—C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In astill further aspect, R^(5c) is hydrogen, —F, —Cl, —NH₂, —OH, methyl,ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still furtheraspect, R^(5c) is hydrogen, —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,—OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or—N(CH₃)(CH₂CH₃). In yet a further aspect, R^(5c) is hydrogen, —F, —Cl,—NH₂, —CN, —OH, methyl, —OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(5c) is hydrogen, —F, —NH₂, —CN, —OH, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino.In a still further aspect, R^(5c) is hydrogen, —F, —NH₂, —CN, —OH,methyl, ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In astill further aspect, R^(5c) is hydrogen, —F, —NH₂, —CN, —OH, methyl,ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or—N(CH₃)(CH₂CH₃). In yet a further aspect, R^(5c) is hydrogen, —F, —NH₂,—CN, —OH, methyl, —OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(5c) is halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In astill further aspect, R^(5c) is —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl,n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still furtheraspect, R^(5c) is —F, —Cl, —NH₂, —CN, —OH, methyl, ethyl, —OCH₃,—OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃).In yet a further aspect, R^(5c) is —F, —Cl, —NH₂, —CN, —OH, methyl,—OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(5c) is —F, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, R^(5c) is —F, —NH₂, —CN, —OH, methyl, ethyl, n-propyl,i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still further aspect, R^(5c)is —F, —NH₂, —CN, —OH, methyl, ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃). In yet a furtheraspect, R^(5c) is —F, —NH₂, —CN, —OH, methyl, —OCH₃, —NHCH₃, or—N(CH₃)₂.

In a further aspect, R^(5c) is hydrogen, halogen, —NH₂, —OH, —CN, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H,—CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or aryl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino.

In a further aspect, R^(5c) is fluorine.

g. R^(6A) Groups

In one aspect, R^(6a) is hydrogen or C1-C4 alkyl. In a further aspect,R^(6a) is hydrogen.

In a further aspect, R^(6a) is hydrogen, methyl, ethyl, isopropyl,n-propyl, isobutyl, n-butyl, s-butyl, or t-butyl. In a still furtheraspect, R^(6a) is hydrogen, methyl, ethyl, isopropyl, or n-propyl. Inyet a further aspect, R^(6a) is hydrogen, methyl, or ethyl. In an evenfurther aspect, R^(6a) is hydrogen or methyl. In a still further aspect,R^(6a) is hydrogen or ethyl.

In a further aspect, R^(6a) is methyl, ethyl, isopropyl, n-propyl,isobutyl, n-butyl, s-butyl, or t-butyl. In a still further aspect,R^(6a) is methyl, ethyl, isopropyl, or n-propyl. In yet a furtheraspect, R^(6a) is methyl, or ethyl. In an even further aspect, R^(6a) ismethyl. In a still further aspect, R^(6a) is ethyl.

h. R^(6B) Groups

In one aspect, R^(6b) is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or —CO₂H. In afurther aspect, R^(6b) is —CO₂H.

In one aspect, R^(6b) is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a furtheraspect, R^(6b) is hydrogen.

In a further aspect, R^(6b) is hydrogen, methyl, ethyl, n-propyl,i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂, or —N(CH₃)(CH₂CH₃). In a still furtheraspect, R^(6b) is hydrogen, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, or—N(CH₃)(CH₂CH₃). In yet a further aspect, R^(6b) is hydrogen, methyl,—CH₂F, —CH₂Cl, —OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(6b) is hydrogen, C1-C4 alkyl, C1-C4 alkoxy,C1-C4 alkylamino, or (C1-C4)(C1-C4) dialkylamino. In a still furtheraspect, R^(6b) is hydrogen, methyl, ethyl, n-propyl, i-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂, —N(CH(CH₃)CH₃)₂,or —N(CH₃)(CH₂CH₃). In a still further aspect, R^(6b) is hydrogen,methyl, ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃). In yet a further aspect, R^(6b) ishydrogen, methyl, —OCH₃, —NHCH₃, or —N(CH₃)₂.

In a further aspect, R^(6b) is hydrogen, C1-C4 alkyl, or C1-C4 alkoxy.In a still further aspect, R^(6b) is hydrogen, methyl, ethyl, n-propyl,i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or —OCH(CH₃)CH₃. In a stillfurther aspect, R^(6b) is hydrogen, methyl, ethyl, —OCH₃, or —OCH₂CH₃.In yet a further aspect, R^(6b) is hydrogen, methyl, or —OCH₃.

In a further aspect, R^(6b) is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl,or C1-C4 alkoxy. In a still further aspect, R^(6b) is hydrogen, methyl,ethyl, n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, or —OCH(CH₃)CH₃. In yet a further aspect, Rb is hydrogen,methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or —OCH₂CH₃.In yet a further aspect, R^(6b) is hydrogen, methyl, —CH₂F, —CH₂Cl, or—OCH₃.

In a further aspect, R^(6b) is C1-C4 alkyl. In a still further aspect,R^(6b) is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,or t-butyl. In yet a further aspect, R^(6b) is methyl, ethyl, n-propyl,or i-propyl. In an even further aspect, R^(6b) is methyl or ethyl. In astill further aspect, R^(6b) is ethyl. In yet a further aspect, R^(6b)is methyl.

i. R⁷ Groups

In one aspect, R⁷ is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4haloalkyl, or C1-C4 alkoxy. In a further aspect, R⁷ is hydrogen.

In a further aspect, R⁷ is hydrogen, —F, —Cl, —OH, methyl, ethyl,n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,or —OCH(CH₃)CH₃. In a still further aspect, R⁷ is hydrogen, —F, —Cl,—OH, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or—OCH₂CH₃. In yet a further aspect, R⁷ is hydrogen, —F, —Cl, —OH, methyl,—CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, R⁷ is hydrogen, —F, —Cl, —OH, C1-C4 alkyl, or C1-C4alkoxy. In a still further aspect, R⁷ is hydrogen, —F, —Cl, —OH, methyl,ethyl, n-propyl, i-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, or—OCH(CH₃)CH₃. In a still further aspect, R⁷ is hydrogen, —F, —Cl, —OH,methyl, ethyl, —OCH₃, or —OCH₂CH₃. In yet a further aspect, R⁷ ishydrogen, —F, —Cl, —OH, methyl, or —OCH₃.

In a further aspect, R⁷ is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, orC1-C4 alkoxy. In a still further aspect, R⁷ is hydrogen, methyl, ethyl,n-propyl, i-propyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, —CH(CH₃)CH₂Cl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,or —OCH(CH₃)CH₃. In yet a further aspect, R⁷ is hydrogen, methyl, ethyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —OCH₃, or —OCH₂CH₃. In yet a furtheraspect, R⁷ is hydrogen, methyl, —CH₂F, —CH₂Cl, or —OCH₃.

In a further aspect, R⁷ is C1-C4 alkyl. In a still further aspect, R⁷ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl. In yet a further aspect, R⁷ is methyl, ethyl, n-propyl, ori-propyl. In an even further aspect, R⁷ is methyl or ethyl. In a stillfurther aspect, R⁷ is ethyl. In yet a further aspect, R⁷ is methyl.

j. R⁸ Groups

In one aspect, R⁸ is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl. In afurther aspect, R⁸ is hydrogen.

In a further aspect, R⁸ is hydrogen, methyl, ethyl, n-propyl, i-propyl,—CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In a still further aspect, R⁸ ishydrogen, methyl, ethyl, —CH₂F, —CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl. In yet afurther aspect, R⁸ is hydrogen, methyl, —CH₂F, or —CH₂Cl.

In a further aspect, R⁸ is hydrogen or C1-C4 alkyl. In a still furtheraspect, R⁸ is hydrogen, methyl, ethyl, n-propyl, or i-propyl. In a stillfurther aspect, R⁸ is hydrogen, methyl, or ethyl. In yet a furtheraspect, R⁸ is hydrogen or ethyl. In an even further aspect, R⁸ ishydrogen or methyl.

In a further aspect, R⁸ is hydrogen or C1-C4 haloalkyl. In a stillfurther aspect, R⁸ is hydrogen, —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In yet afurther aspect, R⁸ is hydrogen, —CH₂F, —CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl.In yet a further aspect, R⁸ is hydrogen, —CH₂F, or —CH₂C1.

In a further aspect, R⁸ is C1-C4 haloalkyl. In a still further aspect,R⁸ is —CH₂F, —CH₂Cl, —CH₂CH₂F, —CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. In yet a further aspect, R⁸ is —CH₂F,—CH₂Cl, —CH₂CH₂F, or —CH₂CH₂Cl. In yet a further aspect, R⁸ is —CH₂F or—CH₂C1.

In a further aspect, R⁸ is C1-C4 alkyl. In a still further aspect, R⁸ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl. In yet a further aspect, R⁸ is methyl, ethyl, n-propyl, ori-propyl. In an even further aspect, R⁸ is methyl or ethyl. In a stillfurther aspect, R⁸ is ethyl. In yet a further aspect, R⁸ is methyl.

k. R^(8A) and R^(8B) Groups

In one aspect, each occurrence of R^(8a) and R^(8b), when present, isindependently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H.In a further aspect, each of R^(8a) and R^(8b) together is ═O. In astill further aspect, R^(8a), when present, is hydrogen. In yet afurther aspect, R^(8b), when present, is hydrogen, C1-C4 alkyl, or C1-C4haloalkyl.

In a further aspect, R^(8a), when present, is C1-C4 alkyl. In a stillfurther aspect, R^(8a), when present, is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yet a furtheraspect, R^(8a), when present, is methyl, ethyl, n-propyl, or i-propyl.In an even further aspect, R^(8a), when present, is methyl or ethyl. Ina still further aspect, R^(8a), when present, is ethyl. In yet a furtheraspect, R^(8a), when present, is methyl.

In a further aspect, R^(8b), when present, is C1-C4 alkyl. In a stillfurther aspect, R^(8b), when present, is methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl. In yet a furtheraspect, R^(8b), when present, is methyl, ethyl, n-propyl, or i-propyl.In an even further aspect, R^(8b), when present, is methyl or ethyl. Ina still further aspect, R^(8b), when present, is ethyl. In yet a furtheraspect, R^(8b), when present, is methyl.

In a further aspect, R^(8a), when present, is C1-C4 haloalkyl. In astill further aspect, R^(8a), when present, is —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. Inyet a further aspect, R^(8a), when present, is —CH₂F, —CH₂Cl, —CH₂CH₂F,or —CH₂CH₂Cl. In yet a further aspect, R^(8a), when present, is —CH₂F or—CH₂Cl.

In a further aspect, R^(8b), when present, is C1-C4 haloalkyl. In astill further aspect, R^(8b), when present, is —CH₂F, —CH₂Cl, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂F, or —CH(CH₃)CH₂Cl. Inyet a further aspect, R^(8b), when present, is —CH₂F, —CH₂Cl, —CH₂CH₂F,or —CH₂CH₂Cl. In yet a further aspect, R^(8b), when present, is —CH₂F or—CH₂Cl.

In a further aspect, R^(8a) is phenyl. Optionally, R^(8a) is phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,R^(8a), when present, is phenyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, R^(8a), when present, is phenylsubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^(a), whenpresent, is phenyl monosubstituted with a group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^(8a), whenpresent, is unsubstituted phenyl.

In a further aspect, R^(8b) is phenyl. Optionally, R^(8b) is phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,R^(8b), when present, is phenyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, R^(8b), when present, is phenylsubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, R^(8b), whenpresent, is phenyl monosubstituted with a group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, R^(8b), whenpresent, is unsubstituted phenyl.

In a further aspect, R^(8a), when present, is —CO₂H.

In a further aspect, R^(8b), when present, is —CO₂H.

In a further aspect, each of R^(8a) and R^(8b) together comprise ═O.

l. R⁹ Groups

In one aspect, R⁹ is hydrogen, C1-C4 alkyl, or Cy⁴. In a further aspect,R⁹ is hydrogen.

In a further aspect, R⁹ is C1-C4 alkyl. In a still further aspect, R⁹ ismethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl. In yet a further aspect, R⁹ is methyl, ethyl, n-propyl, ori-propyl. In an even further aspect, R⁸ is methyl or ethyl. In a stillfurther aspect, R⁹ is ethyl. In yet a further aspect, R⁹ is methyl.

In a still further aspect, R⁹ is Cy⁴.

m. Cy¹ Groups

In one aspect, Cy¹, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Cy¹, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy¹, when present,is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and ismonosubstituted with a group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and isunsubstituted.

In a further aspect, Cy¹, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy¹, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy¹, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy¹, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy¹, when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and isunsubstituted.

In a further aspect, Cy¹, when present, is C3-C6 cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy¹, when present, is C3-C6cycloalkyl substituted with 0 or 1 group selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, whenpresent, is C3-C6 cycloalkyl monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy¹, when present, is unsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy¹, when present, is cyclopropyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is cyclopropyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy¹, when present, is cyclopropyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy¹, when present, is cyclopropyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy¹, when present, isunsubstituted cyclopropyl.

In a further aspect, Cy¹, when present, is C2-C5 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy¹, when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy¹, when present, is C2-C5heterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy¹, whenpresent, is C2-C5 heterocycloalkyl monosubstituted with a group selectedfrom halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still furtheraspect, Cy¹, when present, is unsubstituted C2-C5 heterocycloalkyl.

In a further aspect, Cy¹, when present, is morpholinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is morpholinyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy¹, when present, is morpholinyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy¹, when present, is morpholinyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy¹, when present, isunsubstituted morpholinyl.

In a further aspect, Cy¹, when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is aryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy¹, when present, is aryl substituted with 0 or 1 groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an evenfurther aspect, Cy¹, when present, is aryl monosubstituted with a groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, Cy¹, when present, is unsubstituted aryl.

In a further aspect, Cy¹, when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy¹, whenpresent, is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy¹, when present, is phenyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy¹, when present, is phenyl monosubstituted with agroup selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, Cy¹, when present, is unsubstituted phenyl.

n. Cy² Groups

In one aspect, Cy², when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy², whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy², when present,is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and ismonosubstituted with a group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy², whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and isunsubstituted.

In a further aspect, Cy², when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy², when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy², when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy², when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy², when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and isunsubstituted.

In a further aspect, Cy², when present, is C3-C6 cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy², whenpresent, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy², when present, is C3-C6cycloalkyl substituted with 0 or 1 group selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy², whenpresent, is C3-C6 cycloalkyl monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy², when present, is unsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy², when present, is cyclopropyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy², whenpresent, is cyclopropyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy², when present, is cyclopropyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy², when present, is cyclopropyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy², when present, isunsubstituted cyclopropyl.

In a further aspect, Cy², when present, is C2-C5 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy², when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy², when present, is C2-C5heterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy², whenpresent, is C2-C5 heterocycloalkyl monosubstituted with a group selectedfrom halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still furtheraspect, Cy², when present, is unsubstituted C2-C5 heterocycloalkyl.

In a further aspect, Cy², when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy², whenpresent, is aryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy², when present, is aryl substituted with 0 or 1 groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an evenfurther aspect, Cy², when present, is aryl monosubstituted with a groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, Cy², when present, is unsubstituted aryl.

In a further aspect, Cy², when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy², whenpresent, is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy², when present, is phenyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy², when present, is phenyl monosubstituted with agroup selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, Cy², when present, is unsubstituted phenyl.

o. Cy³ Groups

In one aspect, Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Cy³, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy³, when present,is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and ismonosubstituted with a group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy³, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and isunsubstituted.

In a further aspect, Cy³, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy³, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy³, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy³, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy³, when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and isunsubstituted.

In a further aspect, Cy³, when present, is C3-C6 cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy³, when present, is C3-C6cycloalkyl substituted with 0 or 1 group selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy³, whenpresent, is C3-C6 cycloalkyl monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy³, when present, is unsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy³, when present, is C2-C5 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy³, when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy³, when present, is C2-C5heterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy³, whenpresent, is C2-C5 heterocycloalkyl monosubstituted with a group selectedfrom halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still furtheraspect, Cy³, when present, is unsubstituted C2-C5 heterocycloalkyl.

In a further aspect, Cy³, when present, is morpholinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is morpholinyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy³, when present, is morpholinyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy³, when present, is morpholinyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy³, when present, isunsubstituted morpholinyl.

In a further aspect, Cy³, when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is aryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy³, when present, is aryl substituted with 0 or 1 groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an evenfurther aspect, Cy³, when present, is aryl monosubstituted with a groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, Cy³, when present, is unsubstituted aryl.

In a further aspect, Cy³, when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy³, when present, is phenyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy³, when present, is phenyl monosubstituted with agroup selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, Cy³, when present, is unsubstituted phenyl.

In a further aspect, Cy³, when present, is pyridinyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is pyridinyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy³, when present, is pyridinyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy³, when present, is pyridinyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy³, when present, isunsubstituted pyridinyl.

In a further aspect, Cy³, when present, is oxazolyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is oxazolyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy³, when present, is oxazolyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy³, when present, is oxazolyl monosubstituted witha group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, Cy³, when present, is unsubstituted oxazolyl.

In a further aspect, Cy³, when present, is C3-C6 cycloalkyl or aryl, andis substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy³, when present, is C3-C6 cycloalkyl or aryl, and is substituted with0, 1, or 2 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy³, when present,is C3-C6 cycloalkyl or aryl, and is substituted with 0 or 1 groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an evenfurther aspect, Cy³, when present, is C3-C6 cycloalkyl or aryl, and ismonosubstituted with a group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy³, whenpresent, is C3-C6 cycloalkyl or aryl, and is unsubstituted.

p. Cy⁴ Groups

In one aspect, Cy⁴, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0 or 1 group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Cy⁴, when present,is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and ismonosubstituted with a group selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy⁴, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and isunsubstituted.

In a further aspect, Cy⁴, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy⁴, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy⁴, when present, is C3-C6cycloalkyl or C2-C5 heterocycloalkyl, and is substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy⁴, when present, is C3-C6 cycloalkyl or C2-C5heterocycloalkyl, and is monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy⁴, when present, is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and isunsubstituted.

In a further aspect, Cy⁴, when present, is C3-C6 cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is C3-C6 cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy⁴, when present, is C3-C6cycloalkyl substituted with 0 or 1 group selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy⁴, whenpresent, is C3-C6 cycloalkyl monosubstituted with a group selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy⁴, when present, is unsubstituted C3-C6 cycloalkyl.

In a further aspect, Cy⁴, when present, is cyclopropyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is cyclopropyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy⁴, when present, is cyclopropyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy⁴, when present, is cyclopropyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy⁴, when present, isunsubstituted cyclopropyl.

In a further aspect, Cy⁴, when present, is C2-C5 heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,Cy⁴, when present, is C2-C5 heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, Cy⁴, when present, is C2-C5heterocycloalkyl substituted with 0 or 1 group selected from halogen,—NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Cy⁴, whenpresent, is C2-C5 heterocycloalkyl monosubstituted with a group selectedfrom halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still furtheraspect, Cy⁴, when present, is unsubstituted C2-C5 heterocycloalkyl.

In a further aspect, Cy⁴, when present, is morpholinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is morpholinyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy⁴, when present, is morpholinyl substituted with 0 or1 group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy⁴, when present, is morpholinyl monosubstitutedwith a group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, Cy⁴, when present, isunsubstituted morpholinyl.

In a further aspect, Cy⁴, when present, is aryl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is aryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy⁴, when present, is aryl substituted with 0 or 1 groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an evenfurther aspect, Cy⁴, when present, is aryl monosubstituted with a groupselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, Cy⁴, when present, is unsubstituted aryl.

In a further aspect, Cy⁴, when present, is phenyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, Cy⁴, whenpresent, is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, Cy⁴, when present, is phenyl substituted with 0 or 1group selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, Cy⁴, when present, is phenyl monosubstituted with agroup selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl,C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, Cy⁴, when present, is unsubstituted phenyl.

2. Example Compounds

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as the following structures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

3. Prophetic Compound Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. It is anticipatedthat the prophetic compounds would be active as inhibitors of TXNIPactivity, and such activity can be determined using the assay methodsdescribed herein below.

In one aspect, a compound can be selected from:

or a subgroup thereof.

It is contemplated that one or more compounds can optionally be omittedfrom the disclosed invention.

It is understood that the disclosed compounds can be used in connectionwith the disclosed methods, compositions, kits, and uses.

It is understood that pharmaceutical acceptable derivatives of thedisclosed compounds can be used also in connection with the disclosedmethods, compositions, kits, and uses. The pharmaceutical acceptablederivatives of the compounds can include any suitable derivative, suchas pharmaceutically acceptable salts as discussed below, isomers,radiolabeled analogs, tautomers, and the like.

H. Methods of Making a Compound

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Routes I-IX, as described andexemplified below. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

1. Route I

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein PG is an aminoprotecting group, each of X¹ and X² is independently Cl or Br, and withother substituents as noted in compound descriptions elsewhere herein. Amore specific example is set forth below.

In one aspect, compounds of type 1.6, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.3 can be prepared by a sulfonylation reaction of an appropriate amine,e.g., 1.1 as shown above, and an appropriate sulfonyl halide, e.g., 1.2as shown above. Appropriate amines and appropriate sulfonyl halides arecommercially available or prepared by methods known to one skilled inthe art. In certain cases, a sulfonyl anhydride can also be used. Thesulfonylation reaction is carried out in the presence of an appropriatebase, e.g., triethylamine (TEA), in an appropriate solvent, e.g.,dichloromethane (DCM), for an appropriate period of time, e.g., 2 hours.Compounds of type 1.4 can be prepared by a deprotection reaction of anappropriate protected amine, e.g., 1.3 as shown above. The deprotectionreaction is carried out in the presence of an appropriate deprotectingagent, e.g., hydrochloric acid (HCl) as shown above, in an appropriatesolvent, e.g., dioxane, for an appropriate period of time, e.g., 3hours. Compounds of type 1.6 can be prepared by a coupling reaction ofan appropriate quinazoline derivative, e.g., 1.5 as shown above, and anappropriate amine, e.g., 1.4 as shown above. Appropriate quinazolinederivatives are commercially available or prepared by methods known toone skilled in the art. The coupling reaction is carried out in thepresence of an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA)or triethylamine, in an appropriate solvent, e.g., tetrahydrofuran (TIF)or N-methyl-2-pyrrolidone. As can be appreciated by one skilled in theart, the above reaction provides an example of a generalized approachwherein compounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.7, 1.8, 1.9, 1.10, and 1.11),can be substituted in the reaction to provide substituted quinazolinesulfonamides similar to Formula 1.12.

2. Route II

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein each of X² and X³ isindependently Cl or Br, wherein LG is a leaving group, and with othersubstituents as noted in compound descriptions elsewhere herein. Morespecific examples are set forth below.

In one aspect, compounds of type 1.6, and similar compounds, can beprepared according to reaction Schemes 2B, 2C, and 2D above. Thus,compounds of type 2.2 can be prepared by a coupling reaction of anappropriate quinazoline derivative, e.g., 2.1 as shown above, and anappropriate amine, e.g., 1.4 as shown above. Appropriate quinazolinederivatives and appropriate amines are commercially available orprepared by methods known to one skilled in the art. The couplingreaction is carried out in the presence of an appropriate base, e.g.,triethylamine, in an appropriate solvent, e.g., methanol, at anappropriate temperature, e.g., 50° C., for an appropriate period oftime, e.g., 4 hours. As shown in Scheme 2B, compounds of type 1.6 can beprepared by a Grignard reaction of an appropriate halide, e.g., 2.2 asshown above, and an appropriate Grignard reagent, e.g., 2.3 as shownabove. Appropriate Grignard reagents are commercially available orprepared by methods known to one skilled in the art. The Grignardreaction is carried out in the presence of an appropriate metal salt,e.g., zinc chloride, and an appropriate catalyst, e.g.,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium, in anappropriate solvent, e.g., 1,4-dioxane, for an appropriate period oftime, e.g., 16 hours. Alternatively, as shown in Schemes 2C and 2D,compounds of type 1.6 can be prepared by a coupling reaction of anappropriate halide, e.g., 2.2 as shown above, and an appropriate amine,e.g., 2.4 as shown above. Appropriate amines are commercially availableor prepared by methods known to one skilled in the art. As shown inScheme 2C, the coupling reaction is carried out in the presence of anappropriate base, e.g., potassium carbonate, in an appropriate solvent,e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100° C., for anappropriate period of time, e.g., 2 hours. Alternatively, as shown inScheme 2D, the coupling reaction is carried out at an appropriatetemperature, e.g., 90° C., for an appropriate period of time, e.g., 2hours. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 1.10, 2.5, 2.6, 2.7, 2.9, and 2.11), can besubstituted in the reaction to provide substituted quinazolinesulfonamides similar to Formulas 2.8, 2.10, and 2.12.

3. Route III

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 3.2, and similar compounds, can beprepared according to reaction Scheme 3B above. Thus, compounds of type3.2 can be prepared by reduction of an appropriate ester, e.g., 3.1 asshown above. The reduction is carried out in the presence of anappropriate base, e.g., lithium hydroxide, in an appropriate solventsystem, e.g., tetrahydrofuran and water, for an appropriate period oftime, e.g., 3 hours. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compound of type 3.3), can be substituted in thereaction to provide substituted quinazoline sulfonamides similar toFormula 3.4.

4. Route IV

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein X is a halogen andwith other substituents as noted in compound descriptions elsewhereherein. A more specific example is set forth below.

In one aspect, compounds of type 4.3, and similar compounds, can beprepared according to reaction Scheme 4B above. Thus, compounds of type4.2 can be prepared by a substitution reaction of an appropriatehydroxyl, e.g., 4.3 as shown above. Appropriate hydroxyls arecommercially available or prepared by methods known to one skilled inthe art. The substitution reaction is carried out in the presence of anappropriate halide source, e.g., phosphoryl chloride, at an appropriatetemperature, e.g., 110° C., for an appropriate period of time, e.g., 16hours. Compounds of type 4.3 can be prepared by a coupling reaction ofan appropriate quinazoline derivative, e.g., 4.2 as shown above, and anappropriate amine, e.g., 1.4 as shown above. The coupling reaction iscarried out in the presence of an appropriate base, e.g., triethylamine,in an appropriate solvent, e.g., N-methyl-2-pyrrolidone, at anappropriate temperature, e.g., 140° C., for an appropriate period oftime, e.g., 30 minutes. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.10, 4.4, and 4.5), can besubstituted in the reaction to provide substituted quinazolinesulfonamides similar to Formula 4.6.

5. Route V

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 5.3-5.8, and similar compounds, can beprepared according to reaction Scheme 5B above. Thus, compounds of type5.3 can be prepared by a carbonylation reaction of an appropriate arylbromide, e.g., 5.2 as shown above, and an appropriate amine, e.g.,silazane. Appropriate amines are commercially available or prepared bymethods known to one skilled in the art. The carbonylation reaction iscarried out in the presence of an appropriate catalyst, e.g., palladium(II) acetate, an appropriate ligand, e.g.,1,3-bis(diphenylphosphino)propane, and an appropriate base, e.g.,N,N-diisopropylethylamine, at an appropriate temperature, e.g., 100° C.,for an appropriate period of time, e.g., 4 hours. Compounds of type 5.4can be prepared by a cyanation reaction of an appropriate aryl bromide,e.g., 5.2 as shown above. The cyanation reaction is carried out in thepresence of an appropriate metal cyanide, e.g., zinc cyanide, and anappropriate catalyst, e.g., tetrakis(triphenylphosphine)palladium (0),in an appropriate solvent, e.g., N-methyl-2-pyrrolidone, at anappropriate temperature, e.g., 130° C., for an appropriate period oftime, e.g., 30 minutes. Compounds of type 5.5 can be prepared by acoupling reaction of an appropriate aryl bromide, e.g., 5.2 as shownabove, and an appropriate amine, e.g., morpholine as shown above.Appropriate amines are commercially available or prepared by methodsknown to one skilled in the art. The coupling reaction is carried out inthe presence of an appropriate base, e.g., sodium tert-butoxide, anappropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium (0),and an appropriate ligand, e.g.,2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), in an appropriatesolvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 110°C., for an appropriate period of time, e.g., 1 hour. Compounds of type5.6 can be prepared by a coupling reaction of an appropriate arylbromide, e.g., 5.2 as shown above, and an appropriate organotin reagent,e.g., 2-(tributylstannyl)oxazole as shown above. Appropriate organotinreagents are commercially available or prepared by methods known to oneskilled in the art. The coupling reaction is carried out in the presenceof an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0), in an appropriate solvent, e.g., 1,4-dioxane, at an appropriatetemperature, e.g., 110° C., for an appropriate period of time, e.g., 30minutes. Compounds of type 5.7 can be prepared by a coupling reaction ofan appropriate aryl bromide, e.g., 5.2 as shown above, and anappropriate organoborane, e.g., trimethyl boroxime as shown above.Appropriate organoboranes are commercially available or prepared bymethods known to one skilled in the art. The coupling reaction iscarried out in the presence of an appropriate catalyst, e.g.,tetrakis(triphenylphosphine)palladium (0), and an appropriate base,e.g., potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane,at an appropriate temperature, e.g., 120° C., for an appropriate periodof time, e.g., 1 hour. Compounds of type 5.8 can be prepared by acoupling reaction of an appropriate aryl bromide, e.g., 5.2, and anappropriate amide, e.g., pivalamide as shown above. Appropriate amidesare commercially available or prepared by one skilled in the art. Thecoupling reaction is carried out in the presence of an appropriatecatalyst, e.g., copper (I) iodide, an appropriate ligand, e.g.,N,N′-dimethylethylenediamine, and an appropriate salt, e.g.,tripotassium phosphate, in an appropriate solvent, e.g., 1.4-dioxane, atan appropriate temperature, e.g., 100° C., for an appropriate period oftime, e.g., 16 hours. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 5.2), can be substituted in thereaction to provide substituted quinazoline sulfonamides similar toFormulas 5.3, 5.4, 5.5, 5.6, 5.7, and 5.8.

6. Route VI

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein X is halogen and withother substituents as noted in compound descriptions elsewhere herein. Amore specific example is set forth below.

In one aspect, compounds of type 6.7, and similar compounds, can beprepared according to reaction Scheme 6B above. Thus, compounds of type6.2 can be prepared by electrophilic aromatic substitution of anappropriate arene, e.g., 6.1 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The electrophilic aromatic substitution is carried out in thepresence of an appropriate electrophile, e.g., iodine monochloride, andan appropriate base, e.g., methanol, in an appropriate solvent, e.g.,dichloromethane, for an appropriate period of time, e.g., 1 hour.Compounds of type 6.3 can be prepared by a cyanation reaction of anappropriate aryl iodide, e.g., 6.2 as shown above. The cyanationreaction is carried out in the presence of an appropriate metal cyanide,e.g., zinc cyanide, in an appropriate solvent, e.g.,N-methyl-2-pyrrolidone, at an appropriate temperature, e.g., 150° C.,for an appropriate period of time, e.g., 2 hours. Compounds of type 6.4can be prepared by hydrolysis of an appropriate aryl cyanide, e.g., 6.3as shown above. The hydrolysis is carried out in the presence of anappropriate base, e.g., 6N sodium hydroxide, in an appropriate solvent,e.g., 1,4-dioxane, at an appropriate temperature, e.g., 100° C., for anappropriate period of time, e.g., 16 hours. Compounds of type 6.5 can beprepared by cyclization of an appropriate aryl carboxylic acid, e.g.,6.4 as shown above, and an appropriate amidine, e.g., formamidineacetate as shown above. Appropriate amidines are commercially availableor prepared by methods known to one skilled in the art. The cyclizationis carried out in the presence of an appropriate solvent, e.g., ethoxyethanol, at an appropriate temperature, e.g., 130° C., for anappropriate period of time, e.g., 24 hours. Compounds of type 6.6 can beprepared by a substitution reaction of an appropriate aryl alcohol,e.g., 6.5 as shown above, and an appropriate electrophile, e.g., oxalyldichloride as shown above. The substitution reaction is carried out inthe presence of an appropriate base, e.g., triethylamine, and anappropriate solvent system, e.g., dimethylformamide (DMF) anddichloromethane, for an appropriate period of time, e.g., 16 hours.Compounds of type 6.7 can be prepared by a coupling reaction of anappropriate aryl halide, e.g., 6.6 as shown above, and an appropriateamine, e.g., 1.4 as shown above. The coupling reaction is carried out inthe presence of an appropriate base, e.g., N,N-diisopropylethylamine, inan appropriate solvent, e.g., N-methyl-2-pyrrolidinone, for anappropriate period of time, e.g., 4 hours. As can be appreciated by oneskilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 1.10,6.8, 6.9, 6.10, 6.11, 6.12, and 6.13), can be substituted in thereaction to provide substituted quinazoline sulfonamides similar toFormula 6.14.

7. Route VII

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein each of X¹ and X² isindependently halogen and with other substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forthbelow.

In one aspect, compounds of type 7.4, and similar compounds, can beprepared according to reaction Scheme 7B above. Thus, compounds of type7.3 can be prepared by an alkylation reaction of an appropriate amine,e.g., 7.1 as shown above, and an appropriate alkyl halide, e.g., 7.2 asshown above. Appropriate alkyl halides are commercially available orprepared by methods known to one skilled in the art. The alkylationreaction is carried out in the presence of an appropriate base, e.g.,potassium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at anappropriate temperature, e.g., 80° C., for an appropriate period oftime, e.g., 6 hours. Compounds of type 7.4 can be prepared byhydrogenation of an appropriate aryl halide, e.g., 7.3 as shown above.The hydrogenation is carried out in the presence of an appropriatehydrogen source, e.g., hydrogen gas, and an appropriate catalyst, e.g.,palladium on carbon, in an appropriate solvent, e.g., ethyl acetate, foran appropriate period of time, e.g., 4 hours. As can be appreciated byone skilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 7.5,7.6, and 7.7), can be substituted in the reaction to provide substitutedquinazoline sulfonamides similar to Formula 7.8.

8. Route VIII

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein PG is an aminoprotecting group and with other substituents as noted in compounddescriptions elsewhere herein. A more specific example is set forthbelow.

In one aspect, compounds of type 8.4, and similar compounds, can beprepared according to reaction Scheme 8B above. Thus, compounds of type8.2 can be prepared by deprotection of an appropriate amine, e.g., 8.1as shown above. The deprotection is carried out in the presence of anappropriate deprotecting agent, e.g., hydrochloric acid, in anappropriate solvent system, e.g., 1,4-dioxane and dichloromethane, foran appropriate period of time, e.g., 2 hours. Compounds of type 8.4 canbe prepared by a sulfonylation reaction of an appropriate amine, e.g.,8.2 as shown above, and an appropriate sulfonyl halide, e.g., 8.3 asshown above. The sulfonylation reaction is carried out in the presenceof an appropriate base, e.g., triethylamine, in an appropriate solvent,e.g., dichloromethane, for an appropriate period of time, e.g., 30minutes. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 8.1, 8.2, and 8.3), can be substituted in thereaction to provide substituted quinazoline sulfonamides similar toFormula 8.4.

9. Route IX

In one aspect, substituted quinazoline sulfonamides can be prepared asshown below.

Compounds are represented in generic form, wherein PG is an aminoprotecting group, X is halogen, and with other substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 9.7, and similar compounds, can beprepared according to reaction Scheme 9B above. Thus, compounds of type9.2 can be prepared by epoxidation of an appropriate ketone, e.g., 9.1as shown above. Appropriate ketones are commercially available orprepared by methods known to one skilled in the art. The epoxidation iscarried out in the presence of an appropriate sulfoxonium agent, e.g.,trimethylsulfoxonium iodide, and an appropriate base, e.g., 60% sodiumhydride, in an appropriate solvent, e.g., dimethylsulfoxide (DMSO), foran appropriate period of time, e.g., 12 hours. Compounds of type 9.4 canbe prepared by a nucleophilic substitution reaction of an appropriateepoxide, e.g., 9.2 as shown above, and an appropriate nucleophile, e.g.,9.3 as shown above. The nucleophilic substitution reaction is carriedout in the presence of an appropriate base, e.g., benzyltriethylammonium chloride (TEBAC), in an appropriate solvent, e.g.,dioxane, at an appropriate temperature, e.g., 90° C., for an appropriateperiod of time, e.g., 16 hours. Compounds of type 9.5 can be prepared bydeprotection of an appropriate amine, e.g., 9.4 as shown above. Thedeprotection is carried out in the presence of an appropriatedeprotecting agent, e.g., trifluoroacetic acid (TFA), in an appropriatesolvent, e.g., dichloromethane, for an appropriate period of time, e.g.,1 hour. Compounds of type 9.7 can be prepared by a coupling reaction ofan appropriate aryl halide, e.g., 9.6 as shown above, and an appropriateamine, e.g., 9.5 as shown above. The coupling reaction is carried out inthe presence of an appropriate base, e.g., N,N-diisopropylethylamine, inan appropriate solvent, e.g., dichloromethane, for an appropriate periodof time, e.g., 1 hour. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 9.8, 9.9, 9.10, 9.11, 9.12, and9.13), can be substituted in the reaction to provide substitutedquinazoline sulfonamides similar to Formula 9.14.

I. Methods of Using the Compositions

Provided are methods of using of a disclosed composition or medicament.In one aspect, the method of use is directed to the treatment of adisorder. In a further aspect, the disclosed compounds can be used assingle agents or in combination with one or more other drugs in thetreatment, prevention, control, amelioration, or reduction of risk ofthe aforementioned diseases, disorders and conditions for which thecompound or the other drugs have utility, where the combination of drugstogether are safer or more effective than either drug alone. The otherdrug(s) can be administered by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a disclosed compound.When a disclosed compound is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch drugs and the disclosed compound is preferred. However, thecombination therapy can also be administered on overlapping schedules.It is also envisioned that the combination of one or more activeingredients and a disclosed compound can be more efficacious than eitheras a single agent.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treating or preventing a disorder associated withelevated TXNIP and/or glucagon in a mammal, the method comprisingcombining a therapeutically effective amount of a disclosed compound orproduct of a disclosed method with a pharmaceutically acceptable carrieror diluent.

In a further aspect, the disorder associated with elevated TXNIP and/orglucagon is a disorder affecting regulation of hepatic glucoseproduction. In a still further aspect, the disorder associated withelevated TXNIP is diabetes. In yet a further aspect, the diabetes isselected from Type I diabetes, Type II diabetes, and gestationaldiabetes. In an even further aspect, the diabetes is Type I diabetes. Ina still further aspect, the diabetes is Type II diabetes. In yet afurther aspect, the diabetes is gestational diabetes.

As regards these applications, the present method includes theadministration to an animal, particularly a mammal, and moreparticularly a human, of a therapeutically effective amount of thecompound effective in the inhibition of TXNIP expression and TXNIPprotein signaling. The dose administered to an animal, particularly ahuman, in the context of the present invention should be sufficient toaffect a therapeutic response in the animal over a reasonable timeframe. One skilled in the art will recognize that dosage will dependupon a variety of factors including the condition of the animal, thebody weight of the animal, as well as the severity and stage of thedisorder.

Thus, in one aspect, the invention relates to the manufacture of amedicament comprising combining a disclosed compound or a product of adisclosed method of making, or a pharmaceutically acceptable salt,solvate, or polymorph thereof, with a pharmaceutically acceptablecarrier or diluent.

2. Use of Compounds and Compositions

Also provided are the uses of the disclosed compounds and compositions.Thus, in one aspect, the invention relates to the uses for inhibition ofTXNIP expression or function and/or reduction of glucagon levels. In afurther aspect, the use is treatment of a disorder associated withelevated TXNIP and/or glucagon (e.g., diabetes or diabetes relateddisorders).

In a further aspect, the invention relates to the use of a disclosedcompound or product of a disclosed method in the manufacture of amedicament for the treatment of a disorder associated with TXNIPactivity such as, for example, a disorder associated with elevated TXNIP(e.g., diabetes or diabetes related disorders).

In a further aspect, the disorder associated with elevated TXNIP and/orglucagon is a disorder affecting the regulation of hepatic glucoseproduction. In a still further aspect, the disorder associated withelevated TXNIP is diabetes. In yet a further aspect, the diabetes isselected from Type I diabetes, Type II diabetes, and gestationaldiabetes. In an even further aspect, the diabetes is Type I diabetes. Ina still further aspect, the diabetes is Type II diabetes. In an evenfurther aspect, the disorder is gestational diabetes.

Also provided are uses of the disclosed compounds and compositions fortreating hyperlipidemia and/or fatty liver disease (e.g., nonalcoholicfatty liver disease). The hyperlipidemia and/or fatty liver disease isoptionally associated with elevated TXNIP and/or glucagon, but is notnecessarily so associated. Further, the hyperlipidemia and/or fattyliver disease is optionally related with diabetes, but is notnecessarily related to diabetes.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method, and apharmaceutically acceptable carrier, for use as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method, wherein apharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of the disclosed compound or theproduct of a disclosed method.

In various aspects, the use relates to the treatment of a disorder in avertebrate animal. In a further aspect, the use relates to the treatmentof a disorder in a human subject.

It is understood that the disclosed uses can be employed in connectionwith the disclosed compounds, methods, compositions, and kits. In afurther aspect, the invention relates to the use of a disclosed compoundor composition of a medicament for the treatment of a disorderassociated with elevated TXNIP and/or glucagon and or for treatment ofhyperlipidemia and/or fatty liver disease in a mammal.

3. Kits

In one aspect, disclosed are kits comprising an effective amount of acompound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof, and one or more of: (a) at least one agent known to treat adisorder associated with elevated TXNIP; (b) at least one agent known toreduce TXNIP; and (c) instructions for treating or preventing a disorderassociated with elevated TXNIP.

In another aspect, disclosed are kits comprising an effective amount ofa compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of p and q is independently 0 or1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, or Cy¹; wherein Cy¹, whenpresent, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² is hydrogen orC1-C4 alkyl, or wherein each of R¹ and R² are covalently bonded togetherand, together with the intermediate atoms, comprise a 3- to 6-memberedheterocycloalkyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino; wherein R³ ishydrogen or C1-C4 alkyl; wherein R⁴ is hydrogen, halogen, —NH₂, —OH,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy²; wherein Cy², when present, is C3-C6 cycloalkyl,C2-C5 heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; wherein Cy³, when present, is C3-C6 cycloalkyl, C2-C5heterocycloalkyl, or aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein A is O, NR^(6a), or CHR^(6b); wherein R^(6a) ishydrogen or C1-C4 alkyl; and wherein R^(6b) is hydrogen, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, or (C1-C4)(C1-C4)dialkylamino; wherein R⁷ is hydrogen, halogen, —OH, C1-C4 alkyl, C1-C4haloalkyl, or C1-C4 alkoxy; wherein R⁸ is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl, or a pharmaceutically acceptable salt thereof, and oneor more of: (a) at least one agent known to treat a disorder associatedwith elevated TXNIP; (b) at least one agent known to reduce TXNIP; and(c) instructions for treating or preventing a disorder associated withelevated TXNIP.

In various aspects, the agents and pharmaceutical compositions describedherein can be provided in a kit. The kit can also include combinationsof the agents and pharmaceutical compositions described herein.

In various aspects, the informational material can be descriptive,instructional, marketing or other material that relates to the methodsdescribed herein and/or to the use of the agents for the methodsdescribed herein. For example, the informational material may relate tothe use of the agents herein to treat a subject who has, or who is atrisk for developing, a disorder associated with elevated TXNIP. The kitscan also include paraphernalia for administering the agents of thisinvention to a cell (in culture or in vivo) and/or for administering acell to a patient.

In various aspects, the informational material can include instructionsfor administering the pharmaceutical composition and/or cell(s) in asuitable manner to treat a human, e.g., in a suitable dose, dosage form,or mode of administration (e.g., a dose, dosage form, or mode ofadministration described herein). In a further aspect, the informationalmaterial can include instructions to administer the pharmaceuticalcomposition to a suitable subject, e.g., a human having, or at risk fordeveloping, a disorder associated with elevated TXNIP.

In various aspects, the composition of the kit can include otheringredients, such as a solvent or buffer, a stabilizer, a preservative,a fragrance or other cosmetic ingredient. In such aspects, the kit caninclude instructions for admixing the agent and the other ingredients,or for using one or more compounds together with the other ingredients.

In a further aspect, the compound and the at least one agent known areco-formulated. In a still further aspect, the compound and the at leastone agent are co-packaged.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of the compound and the at least oneagent. In a still further aspect, the effective amount is atherapeutically effective amount. In yet a further aspect, the effectiveamount is a prophylactically effective amount. In an even furtheraspect, each dose of the compound and the at least one agent areco-packaged. In a still further aspect, each dose of the compound andthe at least one agent are co-formulated.

4. Subjects

In various aspects, the subject of the herein disclosed methods is avertebrate, e.g., a mammal. Thus, the subject of the herein disclosedmethods can be a human, non-human primate, horse, pig, rabbit, dog,sheep, goat, cow, cat, guinea pig or rodent. The term does not denote aparticular age or sex. Thus, adult and newborn subjects, as well asfetuses, whether male or female, are intended to be covered. A patientrefers to a subject afflicted with a disease or disorder. The term“patient” includes human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with adisorder associated with elevated TXNIP prior to the administering step.In some aspects of the disclosed methods, the subject has beenidentified with a need for treatment prior to the administering step. Inone aspect, a subject can be treated prophylactically with a compound orcomposition disclosed herein, as discussed herein elsewhere.

a. Dosage

Toxicity and therapeutic efficacy of the agents and pharmaceuticalcompositions described herein can be determined by standardpharmaceutical procedures, using either cells in culture or experimentalanimals to determine the LD₅₀ (the dose lethal to 50% of the population)and the ED₅₀ (the dose therapeutically effective in 50% of thepopulation). The dose ratio between toxic and therapeutic effects is thetherapeutic index and can be expressed as the ratio LD₅₀/ED₅₀.

Data obtained from cell culture assays and further animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity, andwith little or no adverse effect on a human's ability to hear. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any agents usedin the methods described herein, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose can beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (that is, the concentrationof the test compound which achieves a half-maximal inhibition ofsymptoms) as determined in cell culture. Such information can be used tomore accurately determine useful doses in humans. Exemplary dosageamounts of a differentiation agent are at least from about 0.01 to 3000mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1,2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day,or more.

The formulations and routes of administration can be tailored to thedisease or disorder being treated, and for the specific human beingtreated. For example, a subject can receive a dose of the agent once ortwice or more daily for one week, one month, six months, one year, ormore. The treatment can continue indefinitely, such as throughout thelifetime of the human. Treatment can be administered at regular orirregular intervals (once every other day or twice per week), and thedosage and timing of the administration can be adjusted throughout thecourse of the treatment. The dosage can remain constant over the courseof the treatment regimen, or it can be decreased or increased over thecourse of the treatment.

In various aspects, the dosage facilitates an intended purpose for bothprophylaxis and treatment without undesirable side effects, such astoxicity, irritation or allergic response. Although individual needs mayvary, the determination of optimal ranges for effective amounts offormulations is within the skill of the art. Human doses can readily beextrapolated from animal studies (Katocs et al., (1990) Chapter 27 inRemington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., MackPublishing Co., Easton, Pa.). In general, the dosage required to providean effective amount of a formulation, which can be adjusted by oneskilled in the art, will vary depending on several factors, includingthe age, health, physical condition, weight, type and extent of thedisease or disorder of the recipient, frequency of treatment, the natureof concurrent therapy, if required, and the nature and scope of thedesired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman'sThe Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al.,eds., McGraw-Hill, New York, N.Y.).

b. Routes of Administration

Also provided are routes of administering the disclosed compounds andcompositions. The compounds and compositions of the present inventioncan be administered by direct therapy using systemic administrationand/or local administration. In various aspects, the route ofadministration can be determined by a patient's health care provider orclinician, for example following an evaluation of the patient. Invarious aspects, an individual patient's therapy may be customized,e.g., the type of agent used, the routes of administration, and thefrequency of administration can be personalized. Alternatively, therapymay be performed using a standard course of treatment, e.g., usingpre-selected agents and pre-selected routes of administration andfrequency of administration.

Systemic routes of administration can include, but are not limited to,parenteral routes of administration, e.g., intravenous injection,intramuscular injection, and intraperitoneal injection; enteral routesof administration e.g., administration by the oral route, lozenges,compressed tablets, pills, tablets, capsules, drops (e.g., ear drops),syrups, suspensions and emulsions; rectal administration, e.g., a rectalsuppository or enema; a vaginal suppository; a urethral suppository;transdermal routes of administration; and inhalation (e.g., nasalsprays).

In various aspects, the modes of administration described above may becombined in any order.

J. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Biology Experimentals

As an overview, the following steps were taken to identify and optimizelead compounds: (1) primary screening (compound library screen using anINS-1 cell line stably transfected with human TXNIP promoter luciferasereporter system and cultured in low (5 mM) or high glucose (25 mM)glucose; counter screen to exclude hits that also inhibit generaltranscription); (2) secondary screen of hits (dose response andcytotoxicity screen determining IC50 and cell death using(untransfected) INS-1 cells); (3) manual confirmation of hits by (a)performing transient co-transfection experiments using human TXNIPpromoter driven firefly luciferase and pRK-TK driven renilla luciferasereporter constructs in the presence or absence of compound followed bydual luciferase reporter assays; (b) using quantitative real-time RT-PCRto determine the ability of hits to inhibit endogenous TXNIP mRNAexpression); (c) Western blotting to confirm TXNIP inhibition at theprotein level; (d) assessing TXNIP expression at low and high glucose inprimary human islets treated with and without the compound; (e)apoptosis assays, to assess putative TXNIP inhibitors functionally forthe capacity to protect against j-cell apoptosis e.g. by cleavedcaspase-3 analysis; (4) animal testing (lead compounds from the previousscreens and chemical optimization that have proven sufficiently potentin the cell model were tested in vivo in mice using STZ-diabetic miceincluding analysis of glucose homeostasis by blood glucose monitoring.Agents were selected based on efficacy, desirable pharmacokineticproperties, and lack of toxicity and off-target binding. Additionaldetails are provided below.

a. Cell Culture and Treatment

The Rat INS-1 cell line was obtained from UAB and maintained inRPMI-1640 (Invitrogen #11875) supplemented with 10% fetal bovine serum(FBS), 100 U/ml penicillin and 100 mg/ml streptomycin, 10 mM HEPES, 1 mMSodium Pyruvate, 50 μM 2-Mercaptoethanol, and 11.1 mM Glucose in ahumidified incubator with a 5% C02 atmosphere at 37° C. 4×10⁴ cells perwell were seeded to 96-well plate and incubated at 37° C. overnight. Asubset of the cells were then cultured in medium with 5 mM Glucose for24 hrs and then treated in medium with 25 mM glucose with or withoutcompounds to be tested for another 24 hrs.

For seeding cells, the cell composition is calculated and cells arediluted to 4×10⁵ cells/ml. 100 μl are then added to each well anddiluted to 4×10⁴ cells/well.

b. Cell Transfection

The human TXNIP promoter region including −1518 bp upstream of the ATGstart codon was subcloned into the pGL4.17 [luc2/Neo] vector (Promega)to generate the luciferase reporter plasmid and was verified bysequencing.

To generate a stable cell line, INS-1 cells were transfected with thispGL4.17-human TXNIP promoter luciferase plasmid (0.4 μg/well) usingDharmaFECT Duo transfection reagent (1 μl/well; Dharmacon). 48 h aftertransfection, Geneticin (100 μg/ml, Invitrogen) was added to selectstable transfected cells. After all Geneticin-sensitive cells of thecontrol wells (no transfection) had died, single clones were picked andthe dose of Geneticin was reduced to the maintenance dose of 50 μg/ml,which was used thereafter for expansion and culture of these cells.Cells were maintained in medium containing 500 ml RPMI 1640 with 11.1 mMof glucose (Invitrogen, #11875), 50 ml FBS (Invitrogen, #16140), 5 mlPen/Strep (Invitrogen, #15140), 5.5 ml 1M HEPES solution (Invitrogen,#15630), 5.5 ml 100× Sodium Pyruvate (Invitrogen, #11360), and 150 mgL-glutamine (Sigma, #G3126-100G) and for each 10 ml of medium, 35 μl of1:1000 diluted β-Mercaptoethanol (Fisher, #ICN19470583) as well as 10 μlof Geneticin (Invitrogen, #10131) were freshly added each time.

c. Luciferase Assay

In certain assays in which cells were transfected with two promoters todetermine specificity, a Dual-Luciferase® Reporter Assay System(Promega, CAT #E1960) was used according to commercial instructions.Briefly, 24 h after the transfection growth media was removed from thecultured cells. Cells were then rinsed with 200 μl PBS. After decantingthe PBS, the cells were incubated in 25 μl of PLB with gentle rockingfor 15 min at RT. Then 20 μl of cell lysate in PLB were transferred toEppendorf tubes containing 100 μl of LAR (i.e., Luciferase AssaySubstrate in Luciferase Assay Buffer). Cell lysates were then vortexedand firefly luciferase activity was measure. Then 100 μl of Stop&Glowsolution were added to each sample. Samples were vortexed and Renillaluciferase activity was measured using a GLOMAX 20/20 Luminometer, withprotocol “DLR-0-INJ”.

d. Screening Assays

For the primary high throughput screening (HTS) assay, stablytransfected, monoclonal INS-1 cells were split using Trypsin (2 ml perT75 flask) and seeded at a density of 10⁴/well in a 384-well plate andincubated overnight at low, 5 mM glucose. The next day, the medium waschanged to high glucose (25 mM) or high glucose plus the small moleculesto be tested and luciferase assays were performed 24 h later. Compoundscapable of inhibiting glucose-induced TXNIP promoter activity by >50%,but found to be inactive in a counter-screen for general transcriptionalinhibitors were further tested in a secondary qPCR HTS for their abilityto reduce glucose-induced endogenous TXNIP expression in adose-dependent manner. For secondary screens, total RNA was extractedfrom 96-well cultured cells using RNeasy 96 kit (Qiagen #74181)following the manufacturer's protocol using spin technology. Then aone-step qRT-PCR amplification was performed using QuantiFast SYBR GreenRT-PCR kit (Qiagen #204154) and was carried out in a 10 μl reactionwhich consisted of 2 μl RNA, 0.5 μM each of primers (Rat TXNIP 5′primer: CGAGTCAAAGCCGTCAGGAT (SEQ ID NO:1) and Rat TXNIP 3′ primer:TTCATAGCGCAAGTAGTCCAAGGT (SEQ ID NO:2); Or Rat 18S rRNA 5′ primer:AGTCCCTGCCCTTTGTACACA (SEQ ID NO:3) and Rat 18S rRNA 3′ primer:GATCCGAGGGCCTCACTAAAC) (SEQ ID NO:4), 5 μl 2×SYBR Green Master Mix, 0.1μl 10× QuantiFast RT Mix. The SYBR Green assay was performed using aLightCycler 480 II (Roche Applied Science) with an initial incubation at50° C. for 10 min for RT followed by denaturation at 95° C. for 5 min.Forty cycles of amplification were performed using a thermal cyclingprofile of 95° C. for 10s, 60° C. for 30 s. Subsequently, a meltingcurve was recorded by holding at 95° C. for 60 s, cooling to 60° C. for60 s, and then heating at 0.11° C./s up to 95° C. The data was collectedand analyzed using the LightCycler 480 Software Release 1.5.0 SP3. Therelative amount of TXNIP mRNA was normalized to 18 s rRNA level as ahousekeeping gene, and the data was analyzed according to the 2^(−ΔΔC)_(T) method (1). The transformed data was expressed as % inhibition andcompound IC50 calculated by a 4-parameter logistic fit of the data usingGraphPad Prism 7.

The TXNIP inhibitory effect of lead compounds and derivatives wasfurther confirmed manually using dual-luciferase assays including acontrol renilla luciferase plasmid, quantitative real-time RT-PCR andWestern blotting with the anti-TXNIP IgG (JY2; #K0205-3; 1:1000; MBL,Woburn, Mass.), to assure compound-induced TXNIP inhibition also at theprotein level.

e. Cell Viability Analysis

INS-1 cell viability was determined based on quantification of ATP usingCell Titer-Glo Luminescent Cell Viability Assay kit (Promega #G7572),which indicates the presence of metabolically active cells. Briefly,INS-1 cells were seeded into 96-well plates at a cell density of 4.5×10⁴and 3.5×10⁴ cells per well and incubated overnight at 37° C. with 5%CO₂. On the following day, cells were treated with compounds for 24 hrsand 72 hrs respectively. Cell Titer-Glo reagent was added to the cellsand Luminescence was acquired on Synergy 4 Reader (PerkinElmer).

f. Primary Cell Cultures

Isolated primary human islets were cultured in the presence or absenceof compound #11 (Table 1). The compound specifically inhibitedglucose-induced TXNIP expression, as shown in FIG. 1 . Compound #11 alsoprotected human islets against Type 1 diabetes associatedpro-inflammatory cytokine-induced TXNIP expression and β-cell apoptosis,as shown in FIG. 2 .

g. In Vivo Administration Decreases Blood Glucose Levels and SerumGlucagon Levels and Lowers Hepatic Glucose Production in Wild-Type Mice

Compound #11a was administered for three weeks in the drinking water ofwild-type mice at about 100 mg/kg/d. The treated mice showed no changein body weight as compared to untreated controls and no grossabnormalities in organs upon sacrifice. However, the treated mice showeda small but significant decrease in blood glucose levels. Fasting serumglucagon levels were decreased in treated mice as compared to controlmice, suggesting compound #11a affected alpha cell glucagon secretion.Indeed, incubation of alpha TC1-6 cells with compound #11a resulted indecreased glucagon secretion.

Further studies of hepatic glucose production and whole body glucoseturnover, i.e., peripheral glucose uptake into muscle and adiposetissue, were performed using hyperinsulinemic-euglycemic clamp studies.The treated mice showed a significant decrease in basal hepatic glucoseproduction as compared to control. These results indicate compound #11adecreases serum glucagon levels and lowers hepatic glucose production.

h. In Vivo Administration Lowers Circulating Lipid Levels and LiverTriglycerides

Oral administration of compound #11a to wild-type mice resulted insignificantly lower levels of non-esterified fatty acids and oftriglycerides in the serum as compared to control mice not receivingcompound treatment. In addition, liver triglyceride levels incompound-treated mice were two-fold lower than in control mice.

i. In Vivo Administration Prevents/Reverses Diabetes in Two DifferentModels of Diabetes

Oral administration of compound #11a (100 mg/kg/d) to mice startingafter completion of the multiple low-dose STZ regimen, effectivelyprotected against diabetes (FIG. 3 ). Of note, the mice maintained anormal body weight and no detrimental effects or abnormalities werenoticed in response to compound treatment throughout the experiment orupon sacrifice and dissection.

Obese, insulin-resistant and diabetic, leptin receptor-deficient db/dbmice were administered compound #11a as described above for 4 weeks.Similar to the STZ-treated mice, the db/db mice showed no difference inbody weight as compared to untreated db/db mice. However, blood glucoselevels in the treated animals decreased significantly within days ofstarting treatment with compound #11a and remained within the normalrange for the remainder of the study (FIG. 3 ). The treated mice showeda significant decrease in fasting serum glucagon levels similar to thedecrease observed in lean wild-type mice. Thus, certain substitutedquinazoline sulfonamides possess good pharmacokinetic properties and arecapable of effectively inhibiting TXNIP expression, lowering glucagonlevels and hepatic glucose production and of treating and preventingdiabetes. In addition, they can lower liver and serum lipid levels

j. In Vivo Administration Improves STZ-Induced Diabetes in a DoseDependent Manner

After having been rendered overtly diabetic by multiple low-dose STZinjections, mice received compound #11a by gavage at a dose of 100 mg/kgb.i.d or 30 mg/kg b.i.d. or received a vehicle control. Blood glucoselevels significantly decreased in a dose-dependent manner in the micereceiving compound #11a, whereas hyperglycemia continued to worsen invehicle treated mice.

2. Chemistry Experimentals

A. General Synthesis of Substituted(quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamides (Cmpds 1-14)

i. Preparation of tert-butyl 3-(aminomethyl)piperidine-1-carboxylate

To a stirred solution of 1.1 (2.0 g, 9.33 mmol) in CH₂Cl₂ (25 mL) wereadded Et₃N (1.8 g, 18.66 mmol) and methane sulphonyl chloride (1.60 g,13.99 mmol) at RT. The reaction mixture was stirred ate RT for 16 h.Upon complete consumption of starting material, the reaction mixture waspoured into water (50 mL), extracted with CH₂Cl₂ (2×50 mL). The organicextracts were washed with saturated NaHCO₃ (40 mL), water (40 mL), brine(40 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to afford 1.2 (2.0 g, crude) as a thick colorless liquid. MS(MM): m/z=193.0 [M-Boc]⁺.

ii. Preparation of tert-butyl3-(methylsulfonamidomethyl)piperidine-1-carboxylate (1.3)

To a stirred solution of 1.2 (2.0 g, 6.81 mmol) in 1,4-dioxane HCl (4M,2 mL) was stirred at RT for 2 h. Upon complete consumption of startingmaterial, the reaction mixture was concentrated under reduced pressure.The residue was co-distilled with toluene (3×25 mL) to afford 1.3 (1.5g, crude) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.18-8.98 (m,1H), 7.23 (t, J=6.0 Hz, 1H), 3.23-3.15 (m, 2H), 3.23-315 (m, 2H),2.89-2.73 (m, 1H), 2.70 (s, 3H), 2.68-2.56 (m, 3H), 1.91-1.62 (m, 4H),1.22-1.16 (m, 1H).

iii. Preparation of Compounds 1-14

To a solution of 1.3 (0.548 mmol) and DIEA (0.15 ml) in THF/NMIP (8 mL)was added the appropriate quinazoline (0.548 mmol) and the reactionmixture was stirred at RT for 16 h or irradiated at 120-140° C. for30-60 minutes. Upon complete consumption of the starting material, thereaction mixture was poured into water (20 mL), extracted with EtOAc(2×20 mL). The organic extracts were washed with water (2×20 mL), brine(20 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto afford desired compounds 1-14.

a.N-((1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(1)

Yield: 48%; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.89 (dd, J=9.2,5.6 Hz, 1H), 7.75 (ddd, J=9.2, 8.3, 2.8 Hz, 1H), 7.65 (dd, J=9.8, 2.8Hz, 1H), 7.13 (t, J=6.2 Hz, 1H), 4.26 (d, J=12.9 Hz, 1H), 4.13 (d,J=13.2 Hz, 1H), 3.15 (td, J=13.1, 12.3, 2.8 Hz, 1H), 3.01-2.82 (m, 2H),2.89 (s, 3H), 1.92-1.77 (m, 3H), 1.68 (q, J=12.5, 12.0 Hz, 1H),1.37-1.22 (m, 1H); FABMS (M+H) calculated for C₁₅H₁₉FN₄O₂S.H was339.1286 found 339.1299; HPLC purity>98 (% of AUC), t_(R)=2.3, 2.41minutes.

b.N-((1-(5-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(2)

Yield: 44%; 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.89 (dd, J=9.2,5.6 Hz, 1H), 7.75 (ddd, J=9.2, 8.3, 2.8 Hz, 1H), 7.65 (dd, J=9.8, 2.8Hz, 1H), 7.13 (t, J=6.2 Hz, 1H), 4.26 (d, J=12.9 Hz, 1H), 4.13 (d,J=13.2 Hz, 1H), 3.15 (td, J=13.1, 12.3, 2.8 Hz, 1H), 3.01-2.82 (m, 2H),2.89 (s, 3H), 1.92-1.77 (m, 3H), 1.68 (q, J=12.5, 12.0 Hz, 1H),1.37-1.22 (m, 1H); FABMS (M+H) calculated for C₁₅H₁₉FN₄O₂S.H was339.1286 found 339.1294; HPLC purity>99 (% of AUC), t_(R)=2.3, 2.41minutes.

c.N-((1-(8-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(3)

Yield: 62%; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.77 (dt, J=8.4,1.1 Hz, 1H), 7.64 (ddd, J=10.6, 7.9, 1.1 Hz, 1H), 7.53-7.42 (m, 1H),7.11 (t, J=6.1 Hz, 1H), 4.37-4.28 (m, 1H), 4.20 (d, J=13.2 Hz, 1H), 3.17(ddd, J=13.1, 11.4, 2.9 Hz, 1H), 3.00-2.80 (m, 2H), 2.88 (s, 3H),1.91-1.75 (m, 3H), 1.65 (q, J=11.5 Hz, 1H), 1.38-1.22 (m, 1H); FABMS(M+H) calculated for C₁₅H₁₉FN₄O₂S.H was 339.1286 found 339.1288; HPLCpurity>96 (% of AUC), t_(R)=2.23, 2.52 minutes.

d.N-((1-(7-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(4)

Yield: 38%; 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.03 (dd, J=9.3,6.2 Hz, 1H), 7.51 (dd, J=10.2, 2.7 Hz, 1H), 7.38 (ddd, J=9.2, 8.4, 2.8Hz, 1H), 7.10 (t, J=6.1 Hz, 1H), 4.29 (d, J=13.3 Hz, 1H), 4.16 (d,J=13.2 Hz, 1H), 3.17 (s, 1H), 3.00-2.80 (m, 3H), 2.88 (s, 3H), 1.91-1.74(m, 3H), 1.65 (d, J=12.9 Hz, 1H); FABMS (M+H) calculated forC₁₅H₁₉FN₄O₂S.H was 339.1286 found 339.1296; HPLC purity>96 (% of AUC),t_(R)=1.2, 2.38 minutes.

e.N-((1-(6-methoxyquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(5)

Yield: 28%; 1H NMR (400 MHz, DMSO-d6) δ 8.5 (s, 1H), 7.74 (d, J=9.1 Hz,1H), 7.46 (dd, J=9.1, 2.8 Hz, 1H), 7.17-7.09 (m, 2H), 4.25 (d, J=12.8Hz, 1H), 4.09 (d, J=13.2 Hz, 1H), 3.30 (s, 11H), 3.08-2.88 (m, 1H),2.89-2.69 (m, 1H), 1.95-1.77 (m, 1H), 1.32-1.14 (m, 1H); FABMS (M+H)calculated for C₁₆H₂₂N₄O₃S.H was 351.1485 found 351.1479; HPLC purity>95(% of AUC), t_(R)=2.65, 2.72 minutes.

f.N-((1-(5-chloroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(6)

Yield: 40%; ¹H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.46 (s, 1H),7.77-7.63 (m, 3H), 7.62 (d, J=4.1 Hz, OH), 7.54 (d, J=6.7 Hz, 1H),7.08-6.99 (m, 1H), 4.11-3.95 (m, 2H), 3.92 (d, J=13.0 Hz, 1H), 3.81 (d,J=12.9 Hz, 1H), 3.33 (s, 1H), 3.14 (t, J=11.7 Hz, 1H), 2.53 (d, J=11.5Hz, 1H), 1.97 (s, 1H), 1.86 (d, J=12.4 Hz, 1H), 1.79 (s, 1H), 1.73 (s,OH), 1.63 (d, J=17.6 Hz, 1H), 1.30 (s, 2H), 1.14 (q, J=8.0, 7.6 Hz, 1H);FABMS (M+H) calculated for C₁₅H₁₉ClN₄O₂S.H was 355.0990 found 355.0982;HPLC purity>99 (% of AUC), t_(R)=2.77 minutes.

g.N-((1-(6,7-difluoroquinazolin-4-yl)piperidin-3-l)methyl)methanesulfonamide(7)

Yield: 32%; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.89 (dd, J=11.5,8.7 Hz, 1H), 7.80 (dd, J=11.6, 7.9 Hz, 1H), 7.10 (t, J=6.1 Hz, 1H),4.28-4.19 (m, 1H), 4.11 (d, J=13.2 Hz, 1H), 3.16 (ddd, J=13.0, 11.3, 2.9Hz, 1H), 3.00-2.86 (m, 2H), 2.87 (s, 4H), 2.85 (d, J=6.3 Hz, 1H),1.89-1.73 (m, 2H), 1.64 (q, J=11.9 Hz, 1H), 1.35-1.20 (m, 1H); FABMS(M+H) calculated for C₁₅H₁₈F₂N₄O₂S.H was 357.1191 found 357.1183; HPLCpurity>98 (% of AUC), t_(R)=3.11 minutes.

h.N-((1-(6,7-dimethoxyquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(8)

1H NMR (400 MHz, Chloroform-d) δ 8.61 (d, J=1.0 Hz, 1H), 7.27 (d, J=7.0Hz, 1H), 7.07 (s, 1H), 4.84 (s, 1H), 4.17-4.05 (m, 2H), 4.04-3.93 (m,6H), 3.13 (ddd, J=15.9, 9.6, 2.8 Hz, 2H), 3.03 (ddd, J=14.0, 7.7, 6.3Hz, 1H), 2.93 (dd, J=12.9, 9.9 Hz, 1H), 2.00-1.74 (m, 2H), 1.41 (s,1OH), 1.39-1.21 (m, 1H); MS (MM) m/z 402.2 (M+H)⁺.

i.N-((1-(2-phenylquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(9)

Yield: 29%; 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=6.5 Hz, 2H), 7.98 (d,J=8.3 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.49 (s,2H), 7.18 (t, J=6.2 Hz, 1H), 4.43 (d, J=12.8 Hz, 1H), 4.29 (d, J=12.9Hz, 1H), 3.22 (d, J=12.6 Hz, 1H), 2.99 (d, J=14.5 Hz, 3H), 2.89 (s, 3H),1.97 (s, 1H), 1.85 (d, J=20.6 Hz, 3H), 1.70 (s, 1H), 1.32 (d, J=11.3 Hz,1H); FABMS (M+H) calculated for C₂₁H₂₄N₄O₂S.H was 397.1693 found397.1688; HPLC purity>99 (% of AUC), t_(R)=3.66 minutes.

j.N-((1-(8-chloro-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(10)

Yield: 34%; ¹H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.09 (dd, J=2.8Hz, J=8.4 Hz, 1H), 7.65 (dd, J=2.8 Hz, J=9.6 Hz, 1H), 7.11 (t, J=6.0 Hz,1H), 4.27 (d, J=12.8 Hz, 1H), 4.14 (d, J=12.8 Hz, 1H), 3.24-3.16 (m,1H), 2.98-2.89 (m, 6H), 1.91-1.78 (m, 3H), 1.71-1.65 (m, 1H), 1.35-1.26(m, 1H); MS (MM) m/z 373.0 [M]⁺; HPLC purity: >99 (% of AUC).

k.N-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(11)

Yield: 19%; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.22-8.16 (m, 1H),8.04 (dd, J=8.8, 1.9 Hz, 1H), 7.97-7.90 (m, 1H), 7.08 (t, J=6.2 Hz, 1H),4.38 (d, J=13.0 Hz, 1H), 4.21 (d, J=13.2 Hz, 1H), 3.31-3.18 (m, 1H),3.01 (dd, J=13.1, 10.1 Hz, 1H), 2.98-2.80 (m, 2H), 2.87 (s, 3H), 1.85(m, 3H), 1.79 (s, 1H), 1.62 (s, 1H); FABMS (M+H) calculated forC₁₆H₁₉F₃N₄O₂S.H was 389.1254 found 389.1243; HPLC purity>92 (% of AUC),t_(R)=3.99 minutes.

l.N-((1-(7-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(12)

Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.17 (d, J=8.7 Hz,1H), 8.08 (dd, J=2.0, 1.0 Hz, 1H), 7.73 (dd, J=8.8, 2.0 Hz, 1H),7.16-7.08 (m, 1H), 4.41-4.32 (m, 1H), 4.23 (d, J=13.3 Hz, 1H), 3.47-3.28(m, 1H), 3.28-3.16 (m, 1H), 3.04-2.81 (m, 2H), 2.88 (s, 3H), 1.91-1.75(m, 3H), 1.66 (q, J=12.3, 11.9 Hz, 1H), 1.40-1.25 (m, 1H); FABMS (M+H)calculated for C₁₆H₁₉F₃N₄O₂S.H was 389.1254 found 389.1246; HPLCpurity>96 (% of AUC), t_(R)=10.71 minutes.

m.N-((1-(6-cyanoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(13)

Yield: 79%; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.17 (d, J=8.7 Hz,1H), 8.08 (dd, J=2.0, 1.0 Hz, 1H), 7.73 (dd, J=8.8, 2.0 Hz, 1H),7.16-7.08 (m, 1H), 4.41-4.32 (m, 1H), 4.23 (d, J=13.3 Hz, 1H), 3.47-3.28(m, 1H), 3.28-3.16 (m, 1H), 3.04-2.81 (m, 2H), 2.88 (s, 3H), 1.91-1.75(m, 3H), 1.66 (q, J=12.3, 11.9 Hz, 1H), 1.40-1.25 (m, 1H); FABMS (M+H)calculated for C₁₆H₁₉N₅O₂S.H was 389.1254 found 389.1246; HPLC purity>99(% of AUC), t_(R)=1.44 minutes.

n.N-((1-(6-(methylsulfonyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(14)

Yield: 26%; ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H), 8.43 (s, 1H),8.23 (dd, J=1.6 Hz, J=8.8 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.12 (t,J=6.0 Hz, 1H), 4.46 (d, J=13.2 Hz, 1H), 4.27 (d, J=12.8 Hz, 1H),3.40-3.33 (m, 4H), 3.12-3.06 (m, 1H), 2.97-2.94 (m, 2H), 2.89 (s, 3H),1.94-1.82 (m, 3H), 1.67-1.65 (m, 1H), 1.45-1.35 (m, 1H); MS (MM) m/z399.1 [M+H]⁺.

b. Synthesis ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamidehydrochloride (11a)

A stirred solution of 12 (50 mg, mmol) in HCl (4.0 M in 1,4-dioxane) (2mL) was stirred at RT for 2 h. Upon complete consumption of startingmaterial, the reaction mixture was concentrated under reduced pressureto afford 11a (30 mg, 34% as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆):δ 8.86 (s, 1H), 8.36 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.03 (d, J=8.7 Hz,1H), 7.18 (t, J=6.0 Hz, 1H), 4.70 (d, J=10.2 Hz, 1H), 4.49 (d, J=12.0Hz, 1H), 3.63 (t, J=11.7 Hz, 1H), 3.36 (t, J=10.8 Hz, 1H), 2.96 (t,J=7.2 Hz, 1H), 2.92 (s, 3H), 2.0-1.8 (m, 3H), 1.78-1.64 (m, 1H),1.47-1.38 (m, 1H); MS (MM) m/z 389.1 [M+H]⁺; HPLC Purity: >99 (% ofAUC).

c. Synthesis ofN-((1-(2-isopropylquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(15)

i. Preparation ofN-((1-(2-chloroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide

To a stirred solution of 2,4-dichloroquinazoline 1.4 (500 mg, 2.48 mmol)in MeOH (50 mL) was added 1.3 (621 mg, 2.73 mmol) and Et₃N (0.95 mL,7.44 mmol) at RT. The reaction mixture was stirred at 50° C. for 4 h.Upon complete consumption of starting material, the reaction mixture waspoured into water (25 mL), extracted with EtOAc (2×25 mL). The organicextracts were washed with saturated NaHCO₃ (25 mL), water (25 mL), brine(25 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(gradient elution 5-10% of MeOH in CH₂Cl₂) to afford 1.5 (735 mg, 83%).

ii. Preparation ofN-((1-(2-isopropylquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(15)

To a suspension of ZnCl₂ (1 mL, 1.05 mmol) in 1,4-dioxane (2 mL) wasadded isopropyl magnesium bromide (1 mL) and 1.5 (150 mg, 0.42 mmol) atRT. The reaction mixture as stirred at RT for 16 h. Upon completeconsumption of the starting material, the reaction mixture was filteredthrough celite pad. The filtrate was diluted with EtOAc (25 mL), washedwith saturated NaHCO₃ (25 mL), water (25 mL), brine (25 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (gradient elution 5-10%of MeOH in methylene chloride) to afford 15 (36 mg, 22%) as off-whitesolid. ¹H NMR (400 MHz, MeOD): δ 7.66 (d, J=8.4 Hz, 1H), 7.42 (t, J=4.4Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.01-6.98 (m, 1H), 4.23-4.05 (m, 3H),3.10-2.85 (m, 3H), 2.82 (s, 3H), 2.78-2.51 (m, 1H), 1.96-1.85 (m, 2H),1.78-1.73 (m, 1H), 1.70-1.59 (m, 1H), 1.31-1.16 (m, 1H), 1.15 (d, J=5.6Hz, 6H); MS (MM) m/z 363.2 [M+H]⁺; HPLC purity: >95 (% of AUC).

d. Synthesis ofN-((1-(2-(isopropylamino)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(16)

To a stirred solution of 1.5 (200 mg, 0.56 mmol) in 1,4-dioxane (2 mL)taken in a microwave vial was added isopropyl amine (99 mg, 1.68 mmol)and K₂CO₃ (232 mg, 1.68 mmol). The microwave vial was sealed andirradiated at 100° C. for 2 h in CEM-microwave instrument. Upon completeconsumption of starting material, the reaction mixture was poured intowater (20 mL), extracted with EtOAc (2×25 mL). The organic extracts werewashed with saturated NaHCO₃ (25 mL), water (25 mL), brine (25 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (gradientelution 90-100% of EtOAc in hexanes) to afford 16 (73 mg, 34%) as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J=8.4 Hz, 1H),7.44-7.39 (m, 2H), 6.96 (t, J=6.8 Hz, 1H), 4.90 (d, J 7.2 Hz, 1H),4.20-4.15 (m, 1H), 3.78 (brs, 2H), 3.47-3.40 (m, 2H), 3.05-2.95 (m, 2H),2.87 (s, 3H), 2.02 (brs, 1H), 1.86 (brs, 1H), 1.65-1.58 (m, 2H),1.38-1.36 (m, 1H), 1.25-1.16 (m, 6H); MS (MM) m/z 378.1 [M+H]⁺; HPLCpurity: >94 (% of AUC).

e. Synthesis ofN-((1-(2-morpholinoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(17)

A stirred solution of 1.5 (200 mg, 0.56 mmol) in morpholine (0.20 mL)was allowed to stir at 90° C. for 2 h. Upon complete consumption ofstarting material, the reaction mixture was poured into water, extractedwith EtOAc (2×20 mL). The combined extracts were washed with saturatedNaHCO₃ (20 mL), water (20 mL), brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (gradient elution 70-80% of EtOAc inhexanes) to afford 17 (173 mg, 76%) as off white solid. ¹H NMR (400 MHz,DMSO-d6): δ 7.75 (d, J=8 Hz, 1H), 7.57-7.53 (m, 1H), 7.40-7.36 (m, 1H),7.17-7.09 (m, 2H), 4.19 (d, J=12.4 Hz, 1H), 4.06 (d, J=13.2 Hz, 1H),3.76-3.74 (m, 4H), 3.67-3.65 (m, 4H), 3.09 (t, J=10.8 Hz, 1H), 2.96-2.92(m, 1H), 2.89 (s, 3H), 2.88-2.77 (m, 2H), 1.91-1.85 (m, 2H), 1.79-1.76(m, 1H), 1.67-1.58 (m, 1H), 1.34-1.23 (m, 1H); MS (MM) m/z 406.1 [M+H]⁺;HPLC purity: >98 (% of AUC).

f. Synthesis of4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-7-carboxylicacid (18)

iii. Preparation of4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-7-carboxylicacid (18)

To a stirred solution of 1.6 (60 mg, 0.15 mmol) in THE (5 mL), H₂O (5mL) and was added LiOH.H₂O (13.3 mg, 0.31 mmol), at RT. The reactionmixture was stirred at RT for 30 min. Upon complete consumption ofstarting material, the reaction mixture was concentrated under reducedpressure. The residue was diluted with water (5 mL) and acidified with2N HCl to P^(H) 2-3. The precipitated solid was filtered and vacuumdried to afford 18 (17 mg, 30%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.86 (s, 1H), 8.63 (s, 1H), 8.36 (d, J=1.6 Hz, 1H), 8.23 (d,J=8.8 Hz, 1H), 8.08 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.26 (t, J=6.4 Hz,1H), 4.71 (t, J=12.4 Hz, 2H), 3.52 (br s, 2H), 3.30 (t, J=12 Hz, 1H),3.05-3.00 (m, 1H), 2.91 (s, 3H), 1.99 (br s, 1H), 1.90 (d, J=4.8 Hz,2H), 1.72 (d, J=13.6 Hz, 1H), 1.48-1.39 (m, 1H); MS (MM) m/z 365.1[M+H]⁺; HPLC purity>97 (% of AUC).

g. Synthesis of4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-6-carboxylicacid (19)

i. Preparation of methyl4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-6-carboxylate(1.7)

1.7 was made following the same procedure described above for compounds1-14. Yield: 51% as a white solid; ¹H NMR (400 MHz, CDCl₃): δ 8.68 (s,1H), 8.62 (s, 1H), 8.28 (dd, J=1.6 Hz, J=8.4 Hz 1H), 7.87 (d, J=8.8 Hz,1H), 5.61 (t, J=6.4 Hz, 1H), 4.23-4.12 (m, 2H), 3.98 (s, 3H), 3.66-3.55(m, 2H), 3.24-3.11 (m, 2H), 2.99 (s, 3H), 2.22-2.19 (m, 1H), 2.04-21.99(m, 1H), 1.81-1.79 (m, 3H), 1.55-1.51 (m, 1H); MS (MM) m/z 379.1 [M+H]⁺.

ii. Preparation of4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-6-carboxylicacid (19)

To a stirred solution of 1.7 (75 mg, 0.13 mmol) in THE (5 mL), H₂O (5mL) and was added LiOH.H₂O (11 mg, 0.26 mmol) at RT. The reactionmixture was stirred at RT for 30 min. Upon complete consumption ofstarting material, the reaction mixture was concentrated under reducedpressure. The residue was diluted with water (5 mL), acidified with 2NHCl to p^(H)2-3. The precipitated solid was filtered and vacuum dried toget the 19 (63 mg, 88%) as a white solid. ¹H NMR (300 MHz, DMSO-d6): δ8.84 (s, 1H), 8.63 (s, 1H), 8.42 (d, J=8.1 Hz, 1H), 8.09 (d, J=8.4 Hz,1H), 7.28 (br s, 1H), 4.76 (br s, 1H), 4.48 (d, J=11.7 Hz, 1H), 3.68 (d,J=12 Hz, 2H), 2.95 (br s, 2H), 2.89 (s, 3H), 1.90 (d, J=8.1 Hz, 3H),1.72 (d, J=9.3 Hz, 1H), 1.46 (d, J=9.0 Hz, 1H); MS (MM) m/z 365.1[M+H]⁺; HPLC purity>95 (% of AUC).

h. Synthesis ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(20)

i. Preparation ofN-((1-(7-bromo-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methane-sulfonamide(1.10)

A stirred solution of 7-bromo-6-fluoroquinazolin-4-ol 1.8 (2.0 g, 8.33mmol) in POCl₃ (10 mL) was stirred at 110° C. for 16 h. Upon completeconsumption of starting material, the reaction mixture was concentratedunder reduced pressure, the residue was taken in ice cold water (20 mL),extracted with EtOAc (2×25 mL). The organic extracts were washed withwater (2×25 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (gradient elution 30-40% of EtOAc in hexanes)to afford 7-bromo-4-chloro-6-fluoroquinazoline 1.9 (1.3 g, 61%) as ayellow solid. To a stirred solution of 1.9 (200 mg, 0.77 mmol) in NMP (2mL) taken in a microwave vial was added 1.3 (225 mg, 0.99 mmol) and Et₃N(0.29 mL, 2.32 mmol). The microwave vial was sealed and irradiated at140° C. for 30 min in CEM-microwave instrument. Upon completeconsumption of the starting material, the reaction mixture was pouredinto water (20 mL), extracted with EtOAc (2×20 mL). The organic extractswere washed with water (2×20 mL), brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (gradient elution 70-80% of EtOAc inhexanes) to afford 1.10 (190 mg, 59%) as a yellow solid.

ii. Preparation ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(20)

To a stirred solution of 1.10 (100 mg, 0.24 mmol) in NMP (2 mL) taken ina microwave vial was added Zn(CN)₂ (56 mg, 0.48 mmol). Argon gas waspurged through septum and the reaction was degassed for about 5 min. Tothe reaction mixture Pd(PPh₃)₄ (55 mg, 0.048 mmol) was added under inertatmosphere and purged again with argon gas for 5 min. The microwave vialwas sealed and irradiated at 130° C. for 30 min in CEM-microwaveinstrument. Upon complete consumption of the starting material, thereaction mixture was poured into water (20 mL), extracted with EtOAc(2×20 mL). The organic extracts were washed with water (2×20 mL), brine(20 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(gradient elution 5-10% o of CH₃₀H in CH₂C12) to afford 20 (35 mg, 40%)as pale yellow solid. ¹H NMR (300 MHz, DMSO-d6): δ; 8.67 (s, 1H), 8.50(d, J=6.3 Hz, 1H), 7.92 (d, J=10.2 Hz, 1H), 7.11 (t, J=6 Hz, 1H), 4.30(d, J=13.2 Hz, 1H), 4.17 (d, J=13.2 Hz, 1H), 3.24-3.16 (m, 1H),3.03-2.92 (m, 6H), 1.88-1.78 (m, 3H), 1.68-1.59 (m, 1H), 1.36-1.23 (in,1H); MS (MM) m/z 362.0 [M−H]⁺; HPLC purity: >98 (% o AUC).

i. Synthesis of6-fluoro-4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazoline-7-carboxamide(21)

To a stirred solution of 1.10 (150 mg, 0.36 mmol) in DMF (2 mL) taken ina steel bomb added silazane (0.17 mL, 1.08 mmol) and DIPEA (177 mg, 1.08mmol). Argon gas was purged and the reaction was degassed for about 5min. added Pd(OAc) (7 mg, 0.036 mmol), DPPP (10 mg), CO was filled up to250 Psi, allowed to stir at 100° C. for 4 h. Upon complete consumptionof starting material, the reaction mixture was poured into water (25mL), extracted with EtOAc (2×25 mL). The organic extracts were washedwith saturated NaHCO₃ (20 mL), water (20 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (gradient elution80-90% of EtOAc in hexanes) to afford 21 (13 mg, 9%). ¹H NMR (300 MHz,CH₃OD): δ 8.46 (s, 1H), 8.04 (d, J=4.88 Hz, 1H), 7.65 (d, J=10.8 Hz,1H), 7.45-7.40 (m, 1H), 4.33 (d, J=12.6 Hz, 1H), 4.20 (d, J=10.2 Hz,1H), 3.10-2.92 (m, 4H), 2.84 (s, 3H), 1.98-1.61 (m, 4H), 1.38-1.29 (m,1H); MS (MM) m/z 380.1 [M−H]⁺; HPLC purity: >98 (% of AUC).

j. Synthesis ofN-((1-(6-fluoro-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(22)

To a stirred solution of 1.10 (200 mg, 0.47 mmol) in 1,4-dioxane (10 mL)in microwave vial was added trimethylboroxine (120 mg, 0.96 mmol) andK₂CO₃ (200 mg, 1.43 mmol). Argon gas was purged through septum and thereaction was degassed for about 5 min. To the reaction mixture Pd(PPh₃)₄ (110 mg, 0.095 mmol) was added under inert atmosphere, purgedwith argon for 5 more min. The microwave vial was sealed and irradiatedat 120° C. for 1 h in CEM-microwave instrument. Upon completeconsumption of starting material, the reaction mixture was poured intowater (25 mL), extracted with EtOAc (2×25 mL). The organic extracts werewashed with saturated NaHCO₃ (25 mL), water (25 mL), brine (25 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (gradientelution 90-100% of EtOAc in hexanes) to afford 22 (62 mg, 37%) as yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 7.73 (d, J=7.6 Hz,1H), 7.59 (d, J=10.8 Hz, 1H), 7.12 (t, J=6.4 Hz, 1H), 4.24 (d, J=12.8Hz, 1H), 4.11 (d, J=12.8 Hz, 1H), 3.15-3.09 (m, 1H), 2.98-2.87 (m, 2H),2.89 (s, 3H), 2.87-2.84 (m, 1H), 2.42 (s, 3H), 1.88-1.78 (m, 3H),1.71-1.62 (m, 1H), 1.33-1.23 (m, 1H); MS (MM) m/z 353.1 [M+H]⁺; HPLCpurity: >98 (% AUC).

k. Synthesis ofN-((1-(6-fluoro-7-morpholinoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(23)

To a stirred solution of 1.10 (130 mg, 0.30 mmol) in 1,4-dioxane (10 mL)taken in a microwave vial added morpholine (31 mg, 0.36) and NaOtBu (87mg, 0.91 mmol). Ar (g) was purged through septum and the reaction wasdegassed for about 5 min. To the reaction mixture, BINAP (6 mg, 0.009mmol) and Pd₂(dba)₃ (12 mg, 0.015 mmol) were added under Ar (g)atmosphere. The reaction mixture was purged with Ar (g) again for 5 min.The microwave vial was sealed and irradiated at 110° C. in CEM-microwaveinstrument for 1 h. Upon complete consumption of starting material thereaction mixture was poured into water (10 mL) and extracted with EtOAc(2×15 mL). The combined organic extracts were washed with water (2×10mL), brine (10 mL), dried over anhydrous Na₂SO₄ and, concentrated underreduced pressure. The residue was purified by silica gel columnchromatography eluting (EtOAc: hexanes; 9:1). Fractions containing theproduct were combined and concentrated under reduced pressure to afford23 (8 mg, 6%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 8.54 (s,1H), 7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=14.4 Hz, 1H), 6.04 (br s, 1H),4.63 (d, J=12.8 Hz, 1H), 4.41 (d, J=10.4 Hz, 1H), 3.87 (s, 4H), 3.52 (t,J=13.6 Hz, 1H), 3.41-3.33 (m, 5H), 3.22-3.05 (m, 2H), 2.98 (s, 3H), 2.12(br s, 1H), 2.04-1.92 (m, 2H), 1.95-1.92 (m, 1H), 1.77-1.69 (m, 1H); MS(MM) m/z 425.0; HPLC Purity: 97.82 (% of AUC).

l. Synthesis ofN-((1-(6-morpholinoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(24)

i. Preparation ofN-((1-(6-bromoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(1.11)

1.11 was made following the same procedure described above for compounds1-14. Yield: 36%; MS (MM) m/z 399.0 [M+H]⁺.

ii. Preparation ofN-((1-(6-morpholinoquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(24)

To a stirred solution of 1.11 (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL)taken in a microwave vial added morpholine (21.8 mg, 0.25) and NaOtBu(72 mg, 0.75 mmol). Argon gas was purged through septum and the reactionwas degassed for about 5 min. To the reaction mixture, BINAP (4.7 mg,0.007 mmol) and Pd₂(dba)₃ (10.2 mg, 0.01 mmol) were added under inertatmosphere. The reaction mixture was purged with argon gas again for 5min. The microwave vial was sealed and irradiated at 120° C. for 30 min.in CEM-microwave instrument. Upon complete consumption of startingmaterial, the reaction mixture was filtered through celite pad, washedwith EtOAc (50 mL) and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(gradient elution 2-5% of MeOH in CH₂Cl₂) to afford 24 (18 mg, 18%) as ayellow solid. ¹H NMR (300 MHz, CDCl₃): δ 8.59 (s, 1H), 7.82 (d, J=9.6Hz, 1H), 7.49 (d, J=9.6 Hz, 1H), 7.07 (s, 1H), 5.40 (s, 1H), 4.01-3.90(m, 6H), 3.52-3.34 (m, 2H), 3.26-3.07 (m, 6H), 2.97 (s, 3H), 2.17 (s,1H), 2.01-1.97 (m, 1H), 1.77-1.68 (m, 2H), 1.46-1.44 (m, 1H); MS (MM)m/z 406.1 [M+H]⁺; HPLC purity>94 (% AUC).

m. Synthesis ofN-(4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazolin-6-yl)pivalamide(25)

To a stirred solution of 1.11 (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL)taken in a sealed tube added pivalamide (30 mg, 0.30 mmol), K₃PO₄ (159mg, 0.75 mmol), N—N′-dimethylethylenediamine (2.3 mg, 0.025 mmol) andCuI (4.75 mg, 0.025 mmol). The sealed tube equipped with pressure gaugewas sealed and heated at 110° C. for 48 h. Upon complete consumption ofstarting material, the reaction mixture was poured into water (15 mL),extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water (2×20 mL), brine (20 mL), dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography eluting (EtOAc: hexanes; 8:2).Fractions containing the product were combined and concentrated underreduced pressure to afford 25 (25 mg, 24%) as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ 8.82 (s, 1H), 8.65 (s, 1H), 7.85 (d, J=8.8 Hz, 1H),7.66 (s, 1H), 7.33-7.30 (m, 1H), 6.16 (d, J=8.4 Hz, 1H), 4.55 (d, J=14Hz, 1H), 3.26-3.22 (m, 1H), 3.13-2.98 (m, 2H), 2.92 (s, 3H), 2.92-2.75(m, 2H), 2.41-2.36 (m, 1H), 2.04-1.92 (m, 2H), 1.82-1.72 (m, 1H), 1.37(m, 9H), 1.34-1.31 (m, 1H); MS (MM) m/z 420.3[M+H]⁺; HPLC Purity: 98.16(% of AUC).

n. Synthesis ofN-((1-(6-(oxazol-2-yl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(26)

To a stirred solution of 1.11 (100 mg, 0.25 mmol) in 1,4-dioxane (10 mL)taken a microwave vial was added 2-(tributylstannyl)oxazole (108 mg,0.30 mmol). Ar (g) was purged through septum and the reaction wasdegassed for about 5 min. To the reaction mixture Pd(dppf)C12 (18 mg,0.025 mmol) was added under Ar (g) atmosphere. The reaction mixture waspurged with Ar (g) again for 5 min. The microwave vial was sealed andirradiated at 110° C. in CEM-microwave instrument for 30 min. Uponcomplete consumption of starting material, the reaction mixture wasfiltered through pad of celite, washed with EtOAc (50 mL) and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography eluting (MeOH: CH₂C12;0.3:9.7). Fractions containing the product were combined andconcentrated under reduced pressure to afford 26 (55 mg, 36%) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.51 (s, 1H), 8.34 (d,J=9.0 Hz, 1H), 8.31 (s, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.12(t, J=5.7 Hz, 1H), 4.39 (d, J=14.7 Hz, 1H), 4.24 (d, J=13.5 Hz, 1H),3.30-3.26 (m, 1H), 3.07-2.94 (m, 3H), 2.90 (s, 3H), 1.95-1.68 (m, 4H),1.41-1.34 (m, 1H); MS (MM) m/z 388.1 [M+H]⁺; HPLC Purity: 93.58 (% ofAUC).

o. Synthesis ofN-((1-(6-(pyridin-2-yl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(27)

To a stirred solution of 1.11 (200 mg, 0.50 mmol) in 1,4-dioxane (15 mL)taken in a sealed tube fitted with pressure gauge, vial added2-(tributylstannyl)pyridine (221 mg, 0.60). Ar (g) was purged throughseptum and the reaction was degassed for about 5 min. To the reactionmixture Pd(dppf)Cl₂ (40 mg, 0.05 mmol) was added under Ar (g)atmosphere, purged with Ar (g) again for 5 min. The reaction mixture wasstirred at 110° C. for 16 h. Upon complete consumption of startingmaterial, the reaction mixture was filtered through celite pad, washedwith EtOAc (50 mL) and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyeluting (MeOH: CH₂C2; 0.5:9.5). Fractions containing the product werecombined and concentrated under reduced pressure to afford 27 (62 mg,31%) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.74-8.72 (m, 1H),8.62 (s, 2H), 8.51 (dd, J=2.0 Hz, J=8.8 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H),7.96-7.92 (m, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.42-7.39 (m, 1H), 7.13 (t,J=6.0 Hz, 1H), 4.41 (d, J=12 Hz, 1H), 4.26 (d, J=13.6 Hz, 1H), 3.29-3.22(m, 1H), 3.03-2.92 (m, 3H), 2.88 (s, 3H), 1.98-1.70 (m, 4H), 1.38-1.30(m, 1H); MS (MM) m/z 398.0 [M+H]⁺; HPLC Purity: 95.49 (% of AUC).

p. Synthesis ofN-(4-(3-(methylsulfonamidomethyl)piperidin-1-yl)quinazolin-6-yl)picolinamide(28)

To a stirred solution of 1.11 (400 mg, 1.00 mmol) in 1,4-dioxane (10 mL)taken in a sealed tube added picolinamide (146 mg, 1.20 mmol), K₃PO₄(637 mg, 3.01 mmol), N—N′-dimethylethylenediamine (26 mg, 0.3 mmol) andCuI (95 mg, 0.50 mmol). The sealed tube was fitted with pressure gaugewas sealed and heated at 100° C. for 16 h. Upon complete consumption ofstarting material, the reaction mixture was poured into water (15 mL),extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with saturated NaHCO₃ (20 mL), water (20 mL), brine (20 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting (EtOAc:hexanes; 9:1). Fractions containing the product were combined andconcentrated under reduced pressure to afford 28 (40 mg, 10%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.13 (s, 1H), 8.78 (br s,1H), 8.33 (s, 1H), 8.22 (s, 1H), 8.11 (t, J=7.2 Hz, 1H), 7.72 (s, 1H),7.07 (t, J=5.6 Hz, 1H), 4.29 (d, J=13.2 Hz, 1H), 4.19 (d, J=10.4 Hz,1H), 3.19-3.3.14 (m, 1H), 2.98 (t, J=6 Hz, 2H), 2.91 (m, 4H), 1.94-1.74(m, 4H), 1.37-1.33 (m, 1H); MS (MM) m/z 441.1 [M+H]⁺; HPLC Purity: 97.19(% of AUC).

q. Synthesis ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(29)

i. Preparation of 6-bromo-4-chloro-7-fluoroquinazoline (1.13)

To a stirred solution of 6-bromo-7-fluoroquinazolin-4-ol 1.12 (200 mg,0.81 mmol) in SOCl₂ (5.0 mL) was added DMF (0.1 mL) (catalytic) at 0°C., the reaction mixture was stirred at 80° C. for 2 h. Upon completeconsumption of starting material, the reaction mixture was concentratedunder reduced pressure. Co-distilled with toluene (3×25 mL) to afford1.13 (180 mg, crude) as a yellow solid. MS (MM): m/z 262.9 [M+H]⁺.

ii. Preparation ofN-((1-(6-bromo-7-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methane-sulfonamide(1.14)

1.14 was made following the same procedure described above for compounds1-14. Yield: 38%; ¹H NMR (400 MHz, DMSO-d₆): δ 8.60 (s, 1H), 8.23 (d,J=7.6 Hz, 1H), 7.72 (d, J=10 Hz, 1H), 7.13 (t, J=6 Hz, 1H), 4.32 (d,J=12.4 Hz, 1H), 4.17 (d, J=13.2 Hz, 1H), 3.28-3.22 (m, 2H), 3.02-2.98(m, 2H), 2.90 (s, 3H), 1.88-1.78 (m, 3H), 1.69-1.60 (m, 1H), 1.35-1.30(m, 1H).

iii. Preparation ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(29)

To a stirred solution of 1.15 (100 mg, 0.23 mmol) in NMP (5.0 mL) takenin a microwave vial was added Zn(CN)₂ (28 mg, 0.23 mmol). Argon gas waspurged through septum and the reaction mixture was degassed for about 10min. To the reaction mixture added Pd(PPh₃)₄ (13.8 mg, 0.01) under inertatmosphere. The reaction mixture was purged with argon gas again for 5min. The microwave vial was sealed and irradiated at 130° C. for 30 minin CEM-microwave instrument. Upon complete consumption of startingmaterial, the reaction mixture was poured into water (20 mL), extractedwith EtOAc (2×20 mL). The organic extracts were washed with saturatedNaHCO₃ (20 mL), water (20 mL), brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography (gradient elution 70-80% of EtOAc inhexanes) to afford 29 (43 mg, 38%) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.61 (s, 1H), 8.56 (d, J=7.2 Hz, 1H), 7.66 (d, J=10.8Hz, 1H), 7.12 (t, J=6 Hz, 1H), 4.43 (d, J=10.8 Hz, 1H), 4.26 (d, J=13.6Hz, 1H), 3.40-3.36 (m, 1H), 3.12-3.06 (m, 1H), 2.93-2.78 (m, 5H),1.88-1.78 (m, 3H), 1.68-1.62 (m, 1H), 1.37-1.29 (m, 1H); MS (MM) m/z364.1 [M+H]⁺; HPLC purity>99 (% AUC).

r. Synthesis ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamidehydrochloride (29)

A stirred solution of 29 (1.26 g, 3.47 mmol) in 1,4-dioxane was addedHCl (4.0 M in 1,4-dioxane) (20 mL) was stirred at RT for 2 h. Uponcomplete consumption of starting material, the reaction mixture wasconcentrated under reduced pressure to afford 29a (1.36 g, 98%) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.83 (s, 1H), 8.74 (d,J=6.3 Hz, 1H), 7.88 (d, J=9.6 Hz, 1H), 7.21 (t, J=6 Hz, 1H), 4.67 (d,J=12.6 Hz, 1H), 4.45 (d, J=13.5 Hz, 1H), 3.66 (t, J=10.8 Hz, 1H), 3.38(t, J=12.3 Hz, 1H), 2.96-2.92 (m, 2H), 2.89 (s, 3H), 1.88-1.85 (m, 3H),1.70-1.67 (m, 1H), 1.44-1.40 (m, 1H); MS (MM): m/z 364.1 [M+H]⁺; HPLCPurity: 96.9 (% of AUC).

s. Synthesis ofN-((1-(7-fluoro-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methane-sulfonamide(30)

i. Preparation of 5-fluoro-2-iodo-4-(trifluoromethyl)aniline (1.16)

To a stirred solution of 3-fluoro-4-(trifluoromethyl)aniline 1.16 (1.0g, 5.58 mmol) in CH₃OH (20 mL) at 0° C. was added ICl (904 mg, 5.58mmol) in CH₂Cl₂ (10 mL). The reaction mixture was stirred at RT for 1 h.Upon complete consumption of starting material, the reaction mixture waspoured into water (50 mL), extracted with EtOAc (2×50 mL). The organicextracts were washed with saturated water (50 mL), brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting (EtOAc:hexanes; 1:9). Fractions containing the product were combined andconcentrated under reduced pressure to afford 1.16 (1.40 g, 61%) asyellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, J=8.0 Hz, 1H), 6.49(d, J=12.0 Hz, 1H), 4.52 (br s, 2H).

ii. Preparation of 2-amino-4-fluoro-5-(trifluoromethyl)benzonitrile(1.17)

To a stirred solution of 1.16 (1.0 g, 3.28 mmol) in NMP (10 mL) taken ina microwave vial was charged with Zn(CN)₂ (424 mg, 3.61 mmol) and wasdegassed with Ar (g) for 10 min. Pd(PPh₃)₄ (189 mg, 0.164 mmol) wasadded to the reaction mixture under Ar (g) atmosphere and the reactionmixture was again purged with Ar (g) for 5 min. The microwave vial wassealed and irradiated at 150° C. in CEM-microwave instrument for 2 h.Upon complete consumption of starting material, the reaction mixture waspoured into water (10 mL), extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with water (25 mL), brine (25 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting (EtOAc:hexanes; 2:8). Fractions containing the product were combined andconcentrated under reduced pressure to afford 1.17 (408 mg, 60%) as alight yellow solid. MS (MM) m/z 203.0 [M−H]⁺.

iii. Preparation of 2-amino-4-fluoro-5-(trifluoromethyl)benzoic acid(1.18)

To a stirred solution of 1.17 (1.10 g, 5.37 mmol) in 1,4-dioxane (11 mL)at RT added 6N NaOH solution (11 mL). The reaction mixture was stirredat 100° C. for 16 h. Upon complete consumption of starting material, thereaction mixture was poured into water (50 mL), neutralized with 2N HCland extracted with EtOAc (2×50 mL). The combined organic extracts werewashed with saturated water (50 mL), brine (50 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby silica gel column chromatography eluting (EtOAc: hexanes; 1:9).Fractions containing the product were combined and concentrated underreduced pressure to afford 1.18 (635 mg, 53%) as a yellow solid. MS (MM)m/z 221.0 [M−H]⁺.

iv. Preparation of 7-fluoro-6-(trifluoromethyl)quinazolin-4-ol (1.19)

To a stirred solution of 1.18 (620 mg, 2.76 mmol) in ethoxy ethanol (12mL) at RT was added formamidine acetate (576 mg, 5.53 mmol). Thereaction mixture was stirred at 130° C. for 24 h. Upon completeconsumption of starting material, the reaction mixture was poured intowater (50 mL), the solid precipitated was collected by filtration anddried to afford 1.19 (575 mg, crude) as a white solid. MS (MM) m/z 233.0[M+H]⁺.

v. Preparation of 4-chloro-7-fluoro-6-(trifluoromethyl)quinazoline(1.20)

To a stirred solution of 1.19 (50 mg, 0.22 mmol) in CH₂C2 (10 mL) wereadded Et₃N (44 mg, 0.44 mmol), DMF (catalytic) and (COCl)₂ (41.9 mg,0.33 mmol) at RT for 16 h. Upon complete consumption of startingmaterial, the reaction mixture was concentrated under reduced pressure.Co-distilled with toluene (3×25 mL) to afford 1.20 (62 mg, crude) as abrown solid. MS (MM) m/z 250.9 [M]⁺.

vi. Preparation ofN-((1-(7-fluoro-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methane-sulfonamide(30)

To a stirred solution of 1.20 (100 mg, 0.40 mmol) in NMP (5 mL) wasadded 1.3 (146 mg, 0.48 mmol) and DIPEA (154 mg, 1.2 mmol) at RT. Thereaction mixture was stirred at RT for 4 h. Upon complete consumption ofstarting material, the reaction mixture was poured into water (25 mL),extracted with EtOAc (2×25 mL). The organic extracts were washed withsaturated NaHCO₃ (25 mL), water (25 mL), brine (25 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by mass trigger HPLC to afford 30 (4.2 mg, 3%) as anoff-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.61 (s, 1H), 8.08 (d, J=7.2Hz, 1H), 7.54 (d, J=11.2 Hz, 1H), 5.27 (t, J=6 Hz, 1H), 4.03-3.99 (m,2H), 3.62-3.52 (m, 2H), 3.16-3.10 (m, 1H), 3.05-2.99 (m, 1H), 2.11-2.06(m, 1H), 1.98-1.91 (m, 1H), 1.66-1.60 (m, 1H); MS (MM) m/z 407.1 [M+H]⁺;HPLC Purity: 96.4 (% of AUC).

t. General Synthesis of Substituted(quinazolin-4-yl)piperidin-3-yl)methanesulfonamides 31-35, 38, and 39

i. Preparation of tert-butyl3-(methylsulfonamido)piperidine-1-carboxylate (1.22)

To a stirred solution of tert-butyl 3-aminopiperidine-1-carboxylate 1.21(500 mg, 2.49 mmol) in CH₂C2 (25 mL) were added Et₃N (504 mg, 4.99 mmol)and methane sulphonyl chloride (428 mg, 3.74 mmol) at 0° C. The reactionmixture was stirred at RT 1 h. Upon complete consumption of startingmaterial, the reaction mixture was diluted water (40 mL), the mixturewas extracted with CH₂C12 (2×40 mL). The organic extracts were washedwith saturated NaHCO₃ (20 mL), water (20 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (gradient elution30-40% of EtOAc in hexanes) to afford 1.22 (500 mg, 72%) as a thickcolorless liquid. MS (MM) m/z 277.1 [M−H]⁺.

ii. Preparation of N-(piperidin-3-yl)methanesulfonamide (1.23)

A solution of 1.22 (500 mg, 1.70 mmol) in 1,4-dioxane HCl (4M, 2 mL) wasstirred at RT for 2 h. Upon complete consumption of starting material,the reaction mixture was concentrated under reduced pressure. Theresidue was co-distilled with toluene (3×25 mL) to afford 1.23 (280 mg,crude) as a white solid. MS (MM) m/z 179.1 [M+H]⁺.

iii. Preparation of Compounds 31-35, 38, and 39

To a stirred solution of appropriate quinazoline derivative (0.74 mmol)in NMP (3 mL) taken in a microwave vial was added 1.23 (174 mg, 0.82mmol) and DIPEA (0.36 mL, 2.23 mmol). The microwave vial was sealed andirradiated at 150° C. for 40 min. in a CEM-microwave instrument. Uponcomplete consumption of starting material, the reaction mixture waspoured into water (25 mL), extracted with EtOAc (2×25 mL). The organicextracts were washed with saturated NaHCO₃ (25 mL), water (25 mL), brine(25 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(gradient elution 80-90% of EtOAc in hexanes) to afford the desiredtargets 31-35, 38, and 39.

a. N-(1-(quinazolin-4-yl)piperidin-3-yl)methanesulfonamide (31)

Yield: 36%; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.00 (dt, J=8.4,1.1 Hz, 1H), 7.85-7.74 (m, 1H), 7.52 (ddd, J=8.3, 5.4, 2.9 Hz, 1H), 7.32(d, J=7.0 Hz, 1H), 4.25-4.16 (m, 1H), 4.01 (d, J=13.4 Hz, 1H), 3.52(ddd, J=13.1, 9.8, 5.7 Hz, 1H), 3.23-3.04 (m, 2H), 2.97 (s, 3H),2.07-1.94 (m, 1H), 1.86 (dt, J=13.0, 3.9 Hz, 1H), 1.78-1.63 (m, 1H),1.69 (s, 1H), 1.54 (ddd, J=23.3, 10.9, 4.1 Hz, 1H); FABMS (M+H)calculated for C₁₄H₁₈N₄O₂S.H was 307.1223 found 307.1225; HPLC purity>96(% of AUC), t_(R)=1, 1.44 minutes.

b. N-(1-(7-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide (32)

Yield: 53%; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.08 (dd, J=9.3,6.1 Hz, 1H), 7.52 (dd, J=10.2, 2.7 Hz, 1H), 7.40 (ddd, J=9.3, 8.4, 2.7Hz, 1H), 7.32 (d, J=7.0 Hz, 1H), 4.00 (d, J=13.1 Hz, 1H), 3.55-3.47 (m,1H), 3.31-3.09 (m, 2H), 2.96 (s, 3H), 2.06-1.96 (m, 1H), 1.86 (dt,J=12.8, 3.9 Hz, 1H), 1.76-1.61 (m, 1H), 1.55 (ddd, J=23.5, 11.7, 4.0 Hz,1H); FABMS (M+H) calculated for C₁₄H₁₇FN₄O₂S.H was 325.1129 found325.1124; HPLC purity>99 (% of AUC), t_(R)=1.2, 2.33 minutes.

c. N-(1-(6,7-difluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(33)

Yield: 43%; ¹H NMR (300 MHz, DMSO-d6): δ 8.63 (s, 1H), 7.98 (t, J=11.1Hz, 1H), 7.87-7.81 (m, 1H), 7.36 (d, J=6.6 Hz, 1H), 4.12 (d, J=11.4 Hz,1H), 3.95 (d, J=12.9 Hz, 1H), 3.55 (br s, 1H), 3.27-3.12 (m, 2H), 2.99(s, 3H), 2.03-1.87 (m, 2H), 1.72-1.55 (m, 2H); MS (MM) m/z 343.0 [M+H]⁺;HPLC purity: >98 (% of AUC).

d. N-(1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide (34)

Yield: 36%; ¹H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 7.92-7.87 (m,1H), 7.79-7.72 (m, 2H), 7.36 (d, J=7.2 Hz, 1H), 4.13 (d, J=9.9 Hz, 1H),3.94 (d, J=13.5 Hz, 1H), 3.57-3.55 (m, 1H), 3.24-3.09 (m, 2H), 2.98 (s,3H), 2.03-1.99 (m, 1H), 1.91-1.87 (m, 1H), 1.77-1.65 (m, 1H), 1.62-1.51(m, 1H); MS (MM) m/z 325.0 [M+H]⁺; HPLC purity: >99 (% of AUC).

e. N-(1-(6-chloroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide (35)

Yield: 38%; ¹H NMR (300 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.01 (s, 1H),7.84 (s, 2H), 7.36 (d, J=6.9 Hz, 1H), 4.13 (d, J=13.2 Hz, 1H), 3.94 (d,J=13.5 Hz, 1H), 3.56 (br s, 1H), 3.26-3.15 (m, 2H), 2.98 (s, 3H),2.03-1.88 (m, 2H), 1.75-1.55 (m, 2H); MS (MM) m/z 341.0 [M]⁺; HPLCpurity: >98 (% of AUC).

f.N-(1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methanesulfonamide(38)

Yield: 19%; ¹H NMR (400 MHz, CDCl₃): δ 8.79 (s, 1H), 8.18 (s, 1H), 8.02(d, J=8.8 Hz, 1H), 7.94 (dd, J=1.6 Hz, J=8.8 Hz 1H), 5.76 (d, J=5.6 Hz,1H), 3.91 (d, J=4.0 Hz, 2H), 3.87-3.80 (m, 3H), 3.05 (s, 3H), 2.08-2.00(m, 1H), 1.97-1.88 (m, 2H), 1.78-1.70 (m, 1H); (MM) m/z 375.1 [M+H]⁺;HPLC purity>96 (% of ACU).

g.N-(1-(7-fluoro-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methanesulfonamide(39)

Compound 39 was prepared in 2% yield by reactingN-(piperidin-3-yl)cyclopropanesulfonamide 1.23 and quinazoline 1.20,following the same procedure described in scheme 2. ¹H NMR (400 MHz,CDCl₃): δ 8.68 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 7.58 (d, J=11.2 Hz, 1H),5.57 (d, J=5.6 Hz, 1H), 3.85-3.76 (m, 2H), 3.73-3.68 (m, 2H), 2.98 (s,3H), 2.02-1.95 (m, 1H), 1.91-1.83 (m, 2H), 1.71-1.64 (m, 1H), 1.23-1.22(m, 1H); MS (MM) m/z 393.1 [M+H]⁺; HPLC Purity: 94.4 (% of AUC).

u. Synthesis ofN-(1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(36)

i. Preparation ofN-(1-(7-bromo-6-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(1.24)

Intermediate 1.24 was made following the same procedure described abovefor compounds 31-35, 38, and 39. Yield: 52%; ¹H NMR (300 MHz, CDCl₃): δ8.71 (s, 1H), 8.19 (d, J=6.9 Hz, 1H), 7.6 (d, J=9.0 Hz, 1H), 5.82 (d,J=6.3 Hz, 1H), 3.91-3.63 (m, 5H), 3.05 (s, 3H), 2.07-1.97 (m, 5H); MS(MM) m/z 405.0 [M+2]⁺.

ii. Preparation ofN-(1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(36)

Starting from 1.24 and following the same procedure described forpreparation of 29. Yield: 35% as an off-white solid; ¹H NMR (400 MHz,DMSO-d₆): δ 8.71 (s, 1H), 8.52 (d, J=6.4 Hz, 1H), 7.99 (d, J=10.4 Hz,1H), 7.36 (d, J=7.2 Hz, 1H), 4.15 (dd, J=2.8 Hz, J=12.8 Hz, 1H), 3.98(d, J=13.2 Hz, 1H), 3.60-3.52 (m, 1H), 3.30-3.20 (m, 2H), 2.95 (s, 3H),2.03-1.99 (m, 1H), 1.89 (dd, J=4.8 Hz, J=9.2 Hz, 1H), 1.74-1.68 (m, 1H),1.62-1.53 (m, 1H); MS (MM): m/z 350.0 [M+H]⁺; HPLC: >99 (% of AUC).

v. Synthesis ofN-(1-(6-cyano-7-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(37)

i. Preparation ofN-(1-(6-bromo-7-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(1.25)

1.25 was made following the same procedure described above for compounds31-35, 38, and 39.

ii. Preparation ofN-(1-(6-cyano-7-fluoroquinazolin-4-yl)piperidin-3-yl)methanesulfonamide(37)

Compound 37 was synthesized from 1.25 according to the same protocoldescribed for 29. Yield: 55%; ¹H NMR (300 MHz, DMSO-d₆): δ 8.64 (s, 1H),8.61 (d, J=6.9 Hz, 1H), 7.76 (d, J=10.8 Hz, 1H), 7.36 (d, J=6.9 Hz, 1H),4.23 (d, J=12.0 Hz, 1H), 4.09 (d, J=13.5 Hz, 1H), 3.57 (br s, 1H),3.43-3.37 (m, 2H), 2.9 (s, 3H), 2.03-1.88 (m, 2H), 1.70-1.55 (m, 2H); MS(MM) m/z 350.1[M+H]⁺; HPLC Purity: 95.43 (% of AUC).

w. Synthesis ofN-isopropyl-N-((1-(quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(40)

i. Preparation ofN-((1-(2-chloroquinazolin-4-yl)piperidin-3-yl)methyl)-N-isopropylmethanesulfonamide(1.26)

To a stirred solution of 1.5 (150 mg, 0.42 mmol) in DMF (1.5 mL) wasadded bromo isopropyl (103 mg, 0.84 mmol) and K₂CO₃ (174 mg, 1.26 mmol)at 80° C. for 6 h. Upon complete consumption of starting material, thereaction mixture was poured into water (25 mL), extracted with EtOAc(2×25 mL). The organic extracts were washed with saturated NaHCO₃ (25mL), water (25 mL), brine (25 mL) dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (gradient elution 70-80% of EtOAc in hexanes)to afford 1.26 (144 mg, 86%) as an off-white solid.

ii. Preparation ofN-isopropyl-N-((1-(quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide40

To a stirred solution of 1.26 (100 mg, 0.25 mmol) in EtOAc (2 mL) wasadded 10% Pd/C (20 mg, 20% w/w) under inert atmosphere and subjected tohydrogenation at ˜50 Psi pressure using hydrogen bladder at RT for 4 h.Upon complete consumption of the starting material, the reaction mixturewas filtered through celite pad and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (gradient elution 70-80% of EtOAc in hexanes) to afford40 (47 mg, 52%) as off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 9.53 (d,J=8.4 Hz, 1H), 8.90 (s, 1H), 7.88 (t, J=7.6 Hz, 1H), 7.75 (d, J=8.4 Hz,1H), 7.45 (t, J=7.6 Hz, 1H), 4.67 (d, J=12 Hz, 1H), 4.44 (d, 12.4 Hz,1H), 3.96-3.89 (m, 1H), 3.22 (t, J=12.4 Hz, 1H), 3.08-3.03 (m, 2H),2.98-2.85 (m, 5H), 2.12 (br s, 1H), 1.96-1.92 (m, 1H), 1.85-1.81 (m,1H), 1.61-1.58 (m, 1H), 1.22-1.17 (m, 6H); MS (MM) m/z 363.2 [M+H]⁺;HPLC purity: >98 (% of AUC)

x. Synthesis ofN-isopropyl-N-((1-(6-methoxyquinazolin-4-yl)piperidin-3-yl)methyl)benzene-sulfonamide(41)

Compound 41 was synthesized from reaction of To a stirred solution of4-chloro-6-methoxyquinazoline 1.27 andN-isopropyl-N-(piperidin-3-ylmethyl)benzenesulfonamide according thesame procedure described in scheme 1. Yield: 23%; ¹H NMR (400 MHz,CDCl₃): δ 8.61 (s, 1H), 7.77-7.72 (m, 3H), 7.49-7.38 (m, 2H), 7.35 (d,J=2.8 Hz, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.14 (d, J=2.8 Hz, 1H), 4.30 (d,J=12.8 Hz, 1H), 4.10 (d, J=13.2 Hz, 1H), 3.98-3.93 (m, 1H), 3.90 (s,3H), 3.05-3.02 (m, 1H), 2.99-2.96 (m, 2H), 2.78-2.73 (m, 1H), 2.28-2.20(m, 1H), 2.00-1.97 (m, 1H), 1.88-1.83 (m, 1H), 1.80-1.73 (m, 1H),1.26-1.20 (m, 1H), 0.92 (d, J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H); MS(MM) m/z 454.8 [M]⁺; HPLC purity: >98 (% of AUC).

y. Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)-N-isopropylbenzenesulfonamide(42)

Same procedure described for 41. Yield: 18%; ¹H NMR (400 MHz, CDCl₃): δ8.71 (s, 1H), 7.92-7.89 (m, 1H), 7.82-7.80 (m, 2H), 7.55-7.51 (m, 3H),7.49-7.46 (m, 2H), 4.39-4.35 (m, 1H), 4.20 (d, J=14.2 Hz, 1H), 3.15-3.07(m, 3H), 2.86-2.80 (m, 1H), 2.32-2.26 (m, 1H), 2.08-2.05 (m, 1H),1.95-1.90 (m, 1H), 1.82-1.71 (m, 1H), 1.35-1.26 (m, 2H), 1.08 (d, J=6.8Hz, 3H), 1.03 (d, J=6.8 Hz, 3H); MS (MM) m/z 442.8 [M+H]⁺; HPLCpurity: >98 (% of AUC).

z. Synthesis ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-2-yl)methyl)methane-sulfonamide(43)

i. Preparation of tert-butyl2-(methylsulfonamidomethyl)piperidine-1-carboxylate (1.29)

1.29 was made following the same procedure described above for 1.2. MS(MM): m/z=193.1 [M-Boc]⁺.

ii. Preparation of N-(piperidin-2-ylmethyl)methanesulfonamide (1.30)

1.30 was made following the same procedure described above for 1.3. MS(MM): m/z=193.1 [M+H]⁺.

iii. Preparation ofN-((1-(7-bromo-6-fluoroquinazolin-4-yl)piperidin-2-yl)methyl)methane-sulfonamide(1.31)

1.31 was made following the same procedure described above for compound29. MS (MM): m/z=414.9 [M−H]*.

iv. Preparation ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-2-yl)methyl)methane-sulfonamide(43)

Compound 43 was made following the same procedure described above forcompounds 1-14. Yield: 73% from 1.31; ¹H NMR (300 MHz, CDCl₃): δ 8.68(s, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.64 (d, J=9.3 Hz, 1H), 5.88 (br s,1H), 4.87 (br s, 1H), 4.09-3.85 (m, 2H), 3.59-3.49 (m, 1H), 3.34-3.26(m, 1H), 2.95 (s, 3H), 2.05-1.71 (m, 6H); MS (MM) m/z 364.3 [M+H]⁺; HPLCPurity: >99 (% of AUC).

aa. Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)methanesulfonamide(44)

i. Preparation of (1-(6-fluoroquinazolin-4-yl)piperidin-4-yl)methanaminehydrochloride (1.33)

1.33 was made following as in the procedure described above forcompounds 1-14.

ii. Preparation ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)methanesulfonamide(44)

To a stirred solution of 1.33 (150 mg, 0.48 mmol) in CH₂C2 (15 mL) addedmethane sulphonyl chloride (65.9 mg, 0.57 mmol) and Et₃N (145 mg, 1.44mmol) at RT. The reaction mixture was stirred at RT for 30 min. Uponcomplete consumption of starting material, the reaction mixture waspoured into water (20 mL), extracted with CH₂C12 (2×20 mL). The organicextracts were washed with saturated NaHCO₃ (10 mL), water (20 mL) andbrine (20 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (gradient elution 80-90% of EtOAc in hexanes) to afford44 (62 mg, crude, 36%) as an off-white solid. ¹H NMR (300 MHz, CDCl₃): δ8.72 (s, 1H), 7.93-7.88 (m, 1H), 7.54-7.45 (m, 2H), 4.41-4.29 (m, 3H),3.15-3.11 (m, 4H), 2.99 (s, 3H), 1.97-1.73 (m, 3H), 1.55-1.42 (m, 2H);MS (MM) m/z 339.0 [M+H]⁺; HPLC purity: >94 (% of AUC).

bb. Synthesis ofN-(1-(1-(6,7-difluoroquinazolin-4-yl)piperidin-3-yl)ethyl)methanesulfonamide(45)

i. Preparation of N-(1-(piperidin-3-yl)ethyl)methanesulfonamide (1.36)

1.36 was made following the same procedure described above for 1.3.

ii. Preparation ofN-(1-(1-(6,7-difluoroquinazolin-4-yl)piperidin-3-yl)ethyl)methanesulfonamide(45)

To a stirred solution of 1.36 (20 mg, 0.09 mmol) in 1,4-dioxane (2 mL)added 4-chloro-6,7-difluoroquinazoline (22 mg, 0.11 mmol) and K₂CO₃ (68mg, 0.49 mmol) at RT. The reaction mixture was stirred at 80° C. for 3h. Upon complete consumption of starting material, the reaction mixturewas poured into water (25 mL), extracted with EtOAc (25 mL). The organicextracts were washed with saturated NaHCO₃ (25 mL), water (25 mL), brine(25 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(gradient elution 80-90% of EtOAc in hexanes) to afford 45 (8 mg, 22%).¹H NMR (400 MHz, DMSO-d₆): δ 8.60 (s, 1H), 7.91-7.79 (m, 2H), 7.07 (t,J=8.8 Hz, 1H), 4.31 (d, J=13.8 Hz, 1H), 4.02 (t, J=12.8 Hz, 1H),3.20-3.10 (m, 2H), 2.92-2.89 (m, 4H), 1.92-1.78 (m, 3H), 1.65-1.59 (m,1H), 1.39-1.30 (m, 1H), 1.19-1.11 (m, 3H); MS (MM) m/z 371.1[M+H]⁺; HPLCpurity: >98 (% AUC).

cc. Synthesis ofN-((4-(6-fluoroquinazolin-4-yl)morpholin-2-yl)methyl)methanesulfonamide(46)

i. Preparation of tert-butyl2-(methylsulfonamidomethyl)morpholine-4-carboxylate (1.38)

1.38 was made following the same procedure described above for 1.2. MS(MM): m/z 195.1[M-Boc]⁺.

ii. Preparation of N-(morpholin-2-ylmethyl)methanesulfonamide (1.39)

1.39 was made following the same procedure described above for compound1.3. MS (MM): (MM) m/z 195.1[M+H]⁺.

iii. Preparation ofN-((4-(6-fluoroquinazolin-4-yl)morpholin-2-yl)methyl)methanesulfonamide(46)

Compound 46 was prepared from reaction of 1.39 and4-chloro-6-fluoro-quinazoline according to the same procedure describedfor compounds 1-14. Yield: 22% as a yellow solid; ¹H NMR (400 MHz,DMSO-d₆): δ 8.67 (s, 1H), 7.94-7.92 (m, 1H), 7.80-7.74 (m, 2H), 7.21 (t,J=6.0 Hz, 1H), 4.23-4.20 (m, 1H), 4.11-4.07 (m, 1H), 3.97-3.94 (m, 1H),3.77-3.69 (m, 2H), 3.34-3.27 (m, 1H), 3.12 (t, J=6.0 Hz, 2H), 3.06-3.01(m, 1H), 2.93 (s, 3H); MS (MM) m/z 341.1 [M+H]⁺; HPLC Purity: >99 (% ofAUC).

dd. Synthesis of6-fluoro-4-(2-(methylsulfonamidomethyl)morpholino)quinazoline-7-carboxamide(47)

i. Preparation ofN-((4-(7-bromo-6-fluoroquinazolin-4-yl)morpholin-2-yl)methyl)methanesulfonamide(1.40)

Compound 1.40 was prepared according to the same procedure described forcompounds 1-14. Yield: 35% as an off-white solid; ¹H NMR (400 MHz,DMSO-d₆): δ 8.65 (s, 1H), 8.23 (d, J=6.8 Hz, 1H), 7.93 (d, J=9.6 Hz,1H), 7.21 (t, J=6.4 Hz, 1H), 4.27-4.24 (m, 1H), 4.15-4.11 (m, 1H),3.96-3.93 (m, 1H), 3.75-3.68 (m, 2H), 3.37-3.34 (m, 1H), 3.13-3.09 (m,2H), 3.07-3.04 (m, 1H), 2.93 (s, 3H); MS (MM): m/z 419.0 [M]*; HPLCPurity: 97.4 (% of AUC).

ii. Preparation of6-fluoro-4-(2-(methylsulfonamidomethyl)morpholino)quinazoline-7-carboxamide(47)

To a stirred solution of 1.40 (100 mg, 0.23 mmol) in DMF (10 mL) takenin a steel bomb was added hexamethyldisilazane (110 mg, 0.71 mmol) andDIPEA (0.09 mg, 0.71 mmol). Ar (g) gas was purged and the reaction wasdegassed for about 5 min. added Pd(OAc) (16 mg, 0.023 mmol), DPPP (10mg). CO was filled up to 250 Psi, stirred at 110° C. for 4 h. Uponcomplete consumption of starting material, the reaction mixture waspoured into water (20 mL), extracted with EtOAc (2×20 mL). The organicextracts were washed with water (2×20 mL), brine (20 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (gradient elution80-90% of EtOAc in hexanes) to afford 47 (16 mg, 18%) as an off-whitesolid. ¹H NMR (400 MHz, MeOD): δ 8.68 (s, 1H), 8.08 (br s, 1H), 8.01 (d,J=6.8 Hz, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.21 (t, J=6.0 Hz, 1H),4.27-4.24 (m, 1H), 4.15-4.11 (m, 1H), 3.97-3.94 (m, 1H), 3.76-3.70 (m,2H), 3.37-3.35 (m, 1H), 3.13-3.04 (m, 4H), 2.93 (s, 3H); MS (MM): m/z384.1 [M+H]⁺; HPLC Purity: 97.4 (% of AUC).

ee. Synthesis ofN-((1-(6-bromo-7-fluoroquinazolin-4-yl)-3-methylpiperidin-3-yl)methyl)methanesulfonamide(48)

i. Preparation of tert-butyl3-methyl-3-(methylsulfonamidomethyl)piperidine-1-carboxylate (1.42)

Same procedure described for 1.2. MS (MM) m/z=305.1[M−H]⁺.

ii. Preparation of N-((3-methylpiperidin-3-yl)methyl)methanesulfonamide(1.43)

Same procedure described for 1.3. MS (MM) m/z=207.1[M+H]⁺.

iii. Preparation ofN-((1-(6-bromo-7-fluoroquinazolin-4-yl)-3-methylpiperidin-3-yl)methyl)methanesulfonamide(1.44)

Same general procedure described above for compounds 1-14. MS (MM) m/z433.0 [M+H]⁺.

iv. Preparation ofN-((1-(6-bromo-7-fluoroquinazolin-4-yl)-3-methylpiperidin-3-yl)methyl)methanesulfonamide(48)

To a stirred solution of 1.44 (75 mg, 0.17 mmol) in NMP (7.0 mL) wasadded Zn(CN)₂ (40 mg, 0.34 mmol) purged with Ar (g) for 10 min and thenadded Pd₂(dba)₃ (15 mg, 0.016 mmol), Xantphos (9 mg, 0.016 mmol) andtetramethylethylenediamine (TMEDA) (3 mg, 0.033 mmol) under Ar (g)atmosphere and subjected to microwave at 200 W, 200 psi, 160° C. for 90min. After 90 min, the reaction mixture was cooled to RT, water (100 mL)was added and the mixture was extracted with EtOAc (2×250 mL). Theorganic extracts were washed with water (20 mL), brine (20 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by mass triggered prep HPLC to afford 48 (9 mg,13%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.59 (s, 1H),8.56 (d, J=7.20 Hz, 1H), 7.73 (d, J=10.8 Hz, 1H), 7.00 (t, J=6.8 Hz,1H), 3.89-3.86 (m, 1H), 3.75-3.71 (m, 2H), 3.61-3.58 (m, 1H), 2.83 (brs, 5H), 1.78-1.76 (m, 2H), 1.64-1.61 (m, 1H), 1.46-1.41 (m, 1H),1.23-1.22 (m, 3H). LCMS (ESI): m/z=378 [M+H]*, HPLC: 96.7% (AUC).

ff. Synthesis ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)-3-hydroxypiperidin-3-yl)methyl)methanesulfonamide(49)

i. Preparation of tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate(1.46)

To a stirred solution of trimethylsulfoxonium iodide (650 mg, 2.50 mmol)in DMSO (15 mL) was added 60% NaH (138 mg, 3.01 mmol) stirred for 30 minat RT. 1 (500 mg, 2.50 mmol) was added. The reaction mixture was stirredat RT for 12 h. Upon complete consumption of starting material, thereaction mixture was poured into water (25 mL), extracted with CH₂Cl₂(2×25 mL). The organic extracts were washed with saturated NaHCO₃ (25mL), water (25 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to afford 1.46 (250 mg, 47%) as abrown gummy liquid. ¹H NMR (400 MHz, CDCl₃): δ: 3.46-3.43 (m, 3H),3.36-3.33 (m, 1H), 2.75 (br s, 1H), 2.66 (d, J=4.4 Hz, 1H), 1.86-1.80(m, 1H), 1.74-1.60 (m, 3H), 1.45 (s, 9H).

ii. Preparation of tert-butyl3-hydroxy-3-(methylsulfonamidomethyl)piperidine-1-carboxylate (1.47)

To a stirred solution of 1.46 (250 mg, 1.17 mmol) in 1,4-dioxane (2.5mL) were added compound methanesulfonamide (167 mg, 1.75 mmol),Tetraethylbenzylammoniumchloride (TEBAC) (26 mg, 0.11 mmol) and K₂CO₃(16 mg, 0.11 mmol) at RT. The reaction mixture was allowed to stir at90° C. for 16 h. Upon complete consumption of starting material, thereaction mixture was poured into water (25 mL), extracted with CH₂Cl₂(2×25 mL). The organic extracts were washed with saturated NaHCO₃ (25mL), water (25 mL), brine (25 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography eluting (EtOAc: hexanes; 5:5). Fractionscontaining the product were combined and concentrated under reducedpressure to afford 1.47 (180 mg, 50%) as a clear gummy liquid. ¹H NMR(400 MHz, CDCl₃) δ: 3.36-3.33 (m, 2H), 3.25-3.22 (m, 2H), 3.07-3.04 (m,2H), 2.93 (s, 3H), 1.68-1.61 (m, 3H), 1.43 (br s, 1H), 1.39 (s, 9H).LCMS (ESI): m/z=307 [M+H]⁺.

iii. Preparation ofN-((3-hydroxypiperidin-3-yl)methyl)methanesulfonamide (1.48)

To a stirred solution of compound 1.47 (500 mg, 1.62 mmol) in CH₂C2(12.5 mL) was added TFA (786 mg, 8.10 mmol) at RT. The reaction mixturewas stirred at RT for 1 h. Upon complete consumption of startingmaterial, the reaction mixture was concentrated under reduced pressure.Co-distilled with toluene (3×50 mL) to afford 1.48 (300 mg, 1.44 mmol,89%) as a brown gummy liquid. ¹H NMR (400 MHz, CDCl₃) δ: 3.21 (br s,2H), 3.12 (s, 3H), 2.98-2.88 (m, 4H), 2.06-2.01 (m, 1H), 1.87-1.84 (m,1H), 1.56-1.39 (m, 2H). LCMS (ESI): m/z=209 [M+H]⁺.

iv. Preparation of 7-fluoro-4-hydroxyquinazoline-6-carbonitrile (1.49)

To a stirred solution of 1.12 (700 mg, 2.88 mmol) in NMP (17 mL) takenin a microwave vial was charged with Zn(CN)₂ (676 mg, 5.76 mmol) and wasdegassed with argon for 10 min. Pd(PPh₃)₄ (332 mg, 0.28 mmol) was addedto the reaction mixture under Ar (g) atmosphere and the reaction mixturewas again purged with argon for 5 min. The microwave vial was sealed andirradiated at 160° C. in CEM-microwave instrument for 1 h. Upon completeconsumption of starting material, the reaction mixture was poured intowater (25 mL), extracted with EtOAc (2×25 mL). The combined organicextracts were washed with water (25 mL), brine (25 mL), dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography eluting (EtOAc:hexanes; 8:2). Fractions containing the product were combined andconcentrated under reduced pressure to afford 1.49 (490 mg, 90%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 12.73 (br s, 1H), 8.64 (d,J=7.2 Hz, 1H), 8.29 (d, J=3.6 Hz, 1H), 7.76 (d, J=10.4 Hz, 1H). LCMS(ESI): m/z=188 [M+H]⁺.

v. Preparation of 4-chloro-7-fluoroquinazoline-6-carbonitrile (1.50)

To a stirred solution of 8 (175 mg, 0.92 mmol) was added SOCl₂ (15 mL)at RT. The reaction mixture was stirred at 80° C. for 2 h. Upon completeconsumption of starting material, the reaction mixture was concentratedunder reduced pressure. Co-distilled with toluene (3×25 mL) to afford1.50 (175 mg, crude) as brown gummy liquid. The crude product useddirectly in the next step without further analysis.

vi. Preparation ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)-3-hydroxypiperidin-3-yl)methyl)methanesulfonamide(49)

To a stirred solution of 1.50 (175 mg, 0.843 mmol) in CH₂C12 (7.5 mL)were added 1.48 (175 mg, 0.843 mmol) and DIPEA (325 mg, 2.52 mmol) atRT. The reaction mixture was allowed to stir at RT for 1 h. Uponcomplete consumption of starting material, the reaction mixture waspoured into water (25 mL), extracted with EtOAc (2×25 mL). The combinedorganic extracts were washed with water (25 mL), brine (25 mL), driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography eluting (EtOAc:hexanes; 4:6). Fractions containing the product were combined andconcentrated under reduced pressure to afford 49 (85 mg, 26%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.74 (d, J=7.2 Hz, 1H),8.58 (s, 1H), 7.72 (d, J=10.8 Hz, 1H), 7.00 (t, J=6.4 Hz, 1H), 4.88 (s,1H), 4.31 (d, J=12.8 Hz, 1H), 4.00 (d, J=13.2 Hz, 1H), 3.49 (d, J=13.6Hz, 1H), 3.25 (t, J=10.4 Hz, 1H), 2.96 (d, J=6.4 Hz, 2H), 2.90 (s, 3H),1.98-1.96 (m, 1H), 1.74-1.64 (m, 3H). LCMS (ESI): m/z=378 [M+H]⁺. HPLC:98.7% (AUC).

gg. Synthesis ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)-3-fluoropiperidin-3-yl)methyl)methanesulfonamide(50)

i. Preparation of tert-butyl3-fluoro-3-(methylsulfonamidomethyl)piperidine-1-carboxylate (1.52)

Same procedure described for 1.2. MS (MM): m/z=210.9 [M-Boc]⁺.

ii. Preparation of N-((3-fluoropiperidin-3-yl)methyl)methanesulfonamide(1.53)

Same procedure described for 1.3. MS (MM): m/z 211.1 [M+H]⁺.

iii. Preparation ofN-((1-(6-cyano-7-fluoroquinazolin-4-yl)-3-fluoropiperidin-3-yl)methyl)methanesulfonamide(50)

Same general procedure described for compounds 1-14 above. ¹H NMR (400MHz, DMSO-d₆): δ 8.64 (s, 1H), 8.57 (d, J=6.8 Hz, 1H), 7.77 (d, J=10.8Hz, 1H), 7.39 (t, J=6.4 Hz, 1H), 4.46-4.34 (m, 2H), 3.67 (d, J=14.4 Hz,1H), 3.36-3.33 (m, 1H), 3.29-3.24 (m, 1H), 3.23-3.21 (m, 1H), 2.89 (s,3H), 1.98-1.87 (m, 2H), 1.81-1.75 (m, 2H); MS (MM): m/z 382.1 [M+H]⁺;HPLC purity: >98.7 (% of AUC).

hh. Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)pyrrolidin-3-yl)methyl)methanesulfonamide(51)

i. Preparation of(1-(6-fluoroquinazolin-4-yl)pyrrolidin-3-yl)methanamine (1.54)

1.54 was prepared in two steps from 4-chloro-6-fluoro-quinazolinefollowing the same general procedure described for compounds 1-14 above.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.12 (dd, J=10.5, 2.5 Hz, 1H),7.98-7.82 (m, 5H), 4.20 (dd, J=12.2, 7.2 Hz, 1H), 4.17-4.07 (m, 1H),3.83 (t, J=10.0 Hz, 1H), 3.04-2.94 (m, 2H), 2.60 (dt, J=15.2, 7.6 Hz,1H), 2.21 (dd, J=11.1, 5.6 Hz, 1H), 1.81 (dq, J=12.3, 8.5 Hz, 1H); FABMS(M+H) calculated for C₁₃H₁₅FN₄.H was 247.1354 found 247.1346.

ii. Preparation of Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)pyrrolidin-3-yl)methyl)methanesulfonamide(51)

Same procedure described for 44. Yield from 1.54: 32%; 1H NMR (400 MHz,DMSO-d6) δ 8.42 (s, 1H), 7.97 (dd, J=10.9, 2.7 Hz, 1H), 7.76 (dd, J=9.2,5.9 Hz, 1H), 7.67 (ddd, J=9.2, 8.2, 2.7 Hz, 1H), 7.21 (t, J=6.1 Hz, 1H),4.04-3.79 (m, 3H), 3.64 (dd, J=11.2, 7.4 Hz, 1H), 3.06 (h, J=6.7 Hz,2H), 2.90 (s, 3H), 2.48-2.38 (m, 1H), 2.08 (dq, J=11.8, 6.5 Hz, 1H),1.74 (dq, J=12.2, 8.1 Hz, 1H); FABMS (M+H) calculated for C₁₄H₁₇FN₄O₂S.Hwas 325.1129 found 325.1128; HPLC purity>99 (% of AUC), t_(R)=1.46, 1.73minutes.

ii. Synthesis ofN-(3-(6-fluoroquinazolin-4-yl)cyclobutyl)methanesulfonamide (52)

i. Preparation of 1-(6-fluoroquinazolin-4-yl)azetidin-3-amine (1.55)

Intermediate 1.55 was prepared in two steps following the same generalprocedure described for compounds 1-14 above. FABMS (M+H) calculated forC₁₁H₁₁FN₄.H was 219.1041 found 219.1042.

ii. Preparation ofN-(3-(6-fluoroquinazolin-4-yl)cyclobutyl)methanesulfonamide (52)

Compound 52 was prepared by mesylation of 1.55 following the sameprocedure described for preparation of 1.2 (Scheme 1). Yield from 1.55.34%; 1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.98 (d, J=8.0 Hz, 1H),7.86-7.70 (m, 1H), 7.67 (dd, J=9.7, 2.7 Hz, 1H), 4.39 (s, 2H), 3.32 (s,5H), 2.97 (s, 2H); FABMS (M+H) calculated for C₁₂H₁₃FN₄O₂S.H was297.0864 found 297.0814; HPLC purity=100 (% of AUC), t_(R)=1.73 minutes.

jj. Synthesis ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)-1,1,1-trifluoromethanesulfonamide(53)

i. Preparation of tert-butyl3-(((trifluoromethyl)sulfonamido)methyl)piperidine-1-carboxylate (1.56)

To a stirred solution of 1.1 (500 mg, 2.33 mmol) in CH₂C2 (25 mL) wereadded Et₃N (470 mg, 4.66 mmol) and triflicanhydride (980 mg, 3.49 mmol)at 0° C. The reaction mixture was stirred at RT 1 h. Upon completeconsumption of starting material, the reaction mixture was poured intowater (40 mL), extracted with CH₂Cl₂ (2×40 mL). The organic extractswere washed with saturated NaHCO₃ (40 mL), water (40 mL), brine (40 mL),dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (gradientelution 40-50% of EtOAc in hexanes) to afford 1.56 (500 mg, 73%) as athick colorless liquid. MS (MM) m/z 345.1 [M−H]⁺.

ii. Preparation of1,1,1-trifluoro-N-(piperidin-3-ylmethyl)methanesulfonamide (1.57)

Same procedure described for 1.3. MS (MM) m/z 245.1 [M−H]⁺.

iii. Preparation ofN-((1-(7-bromo-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)-1,1,1-trifluoromethanesulfonamide(1.58)

Same general procedure described for compounds 1-14 above. Yield from1.9: 22%; ¹H NMR (400 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.61 (s, 1H), 8.20(d, J=7.2 Hz, 1H), 7.8 (d, J=9.6 Hz, 1H), 4.2 (d, J=11.6 Hz, 1H), 4.13(d, J=13.6 Hz, 1H), 3.22-3.13 (m, 3H), 2.98 (dd, J=10.0 Hz, J=12.8 Hz,1H), 1.92-1.79 (m, 3H), 1.71-1.64 (m, 1H), 1.35-1.27 (m, 1H); MS (MM)m/z 473.0 [M+2]⁺.

iv. Preparation ofN-((1-(7-cyano-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)-1,1,1-trifluoromethanesulfonamide(54)

Same procedure described for 20. Yield from 1.58: 29%; ¹H NMR (300 MHz,DMSO-d₆): δ 9.48 (s, 1H), 8.69 (s, 1H), 8.51 (d, J=6.3 Hz, 1H), 7.91 (d,J=10.2 Hz, 1H), 4.27 (d, J=12.3 Hz, 1H), 4.14 (d, J=13.5 Hz, 1H), 3.23(d, J=11.4 Hz, 1H), 3.14 (d, J=6.3 Hz, 2H), 3.03 (t, J=10.8 Hz, 1H),1.90-1.65 (m, 4H), 1.39-1.23 (m, 1H); MS (MM) m/z 416.1 [M+H]⁺; HPLCpurity>98 (% of AUC).

kk. Synthesis ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)benzenesulfonamide(54)

i. Preparation of tert-butyl3-(phenylsulfonamidomethyl)piperidine-1-carboxylate (1.59)

Same general procedure described for 1.2. MS (MM): m/z=254.5 [M-Boc]⁺.

ii. Preparation of N-(piperidin-3-ylmethyl)benzenesulfonamide (1.60)

Same general procedure described for 1.3. MS (MM): m/z=255.1 [M+H]⁺.

iii. Preparation ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)benzenesulfonamide(54)

Same general procedure described above (Scheme 1). Yield from 1.60: 16%;¹H NMR (400 MHz, CDCl₃): δ 8.68 (s, 1H), 8.09 (s, 1H), 7.96 (d, J=8.8Hz, 1H), 7.90-7.86 (m, 3H), 7.56-7.47 (m, 3H), 5.68 (t, J=6.8 Hz, 1H),4.0-3.90 (m, 2H), 3.65-3.56 (m, 2H), 3.08-3.01 (m, 1H), 2.92-2.85 (m,1H), 2.11-2.08 (m, 1H), 1.97-1.91 (m, 1H), 1.73-1.68 (m, 1H), 1.52-1.46(m, 1H); MS (MM) m/z 451.1 [M+H]⁺; HPLC purity>92 (% AUC).

ll. Synthesis ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)cyclohexanesulfonamide(55)

i. Preparation of tert-butyl3-(cyclohexanesulfonamidomethyl)piperidine-1-carboxylate (1.61)

Same general procedure described for 1.2. MS (MM) m/z=261.2 [M+H]⁺.

ii. Preparation of N-(piperidin-3-ylmethyl)cyclohexanesulfonamide (1.62)

Same general procedure described for 1.3. MS (MM): m/z=261.2 [M+1]⁺.

iii. Preparation ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)cyclohexanesulfonamide(55)

Same general procedure described for compounds 1-14 above. Yield from1.62: 36%; ¹H NMR (400 MHz, CDCl₃): δ 8.70 (s, 1H), 8.14 (s, 1H), 7.97(d, J=8.8 Hz, 1H), 7.89 (dd, J=2.0 Hz, J=8.4 Hz, 1H), 5.23 (t, J=6.8 Hz,1H), 4.09-4.01 (m, 2H), 3.71-3.64 (m, 2H), 3.22-3.15 (m, 1H), 3.11-3.04(m, 1H), 2.92-2.86 (m, 1H), 2.22-2.13 (m, 3H), 2.02-1.97 (m, 1H),1.91-1.87 (m, 1H), 1.79-1.69 (m, 2H), 1.67-1.48 (m, 3H), 1.33-1.1 (m,4H); MS (MM) m/z 455.0 [M−H]⁺; HPLC purity>92 (% of ACU).

mm. Synthesis of4-chloro-N-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)benzenesulfonamide(56)

i. Preparation of tert-butyl((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)carbamate(1.63)

Same general procedure described for compounds 1-14 above. ¹H NMR (400MHz, DMSO-d₆): δ 8.12 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.89 (d, J=2.0Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 4.86 (br s, 1H), 4.23 (d, J=12.0 Hz,2H), 3.31 (t, J=10.8 Hz, 1H), 3.21-3.00 (m, 4H), 2.72 (s, 3H), 2.04-1.96(m, 2H), 1.90-1.85 (m, 1H), 1.79-1.75 (m, 1H), 1.42 (s, 1H); MS (MM) m/z411.2 [M+H]⁺.

ii. Preparation of(1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methanamine (1.64)

Same general procedure described for compounds 1-14 above. MS (MM)m/z=311.2 [M+H]⁺.

iii. Preparation of4-chloro-N-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)benzenesulfonamide(56)

To a stirred solution of 1.64 (25 mg, 0.07 mmol) in CH₂C2 (20 mL) wereadded Et₃N (14.5 mg, 0.14 mmol) and 4-chloro benzene sulphonyl chloride(18.2 mg, 0.08 mmol) at 0° C. The reaction mixture was stirred at RT for1 h. Upon complete consumption of starting material, the reactionmixture was poured into water (20 mL), extracted with CH₂C12 (2×20 mL).The organic extracts were washed with saturated NaHCO₃ (20 mL), water(20 mL), brine (20 mL), dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (gradient elution 30-40% of EtOAc in hexanes) to afford55 (15 mg, 56%) as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 8.69 (s,1H), 8.10 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.81(d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 5.81 (t, J=6.0 Hz, 1H),4.03-3.96 (m, 1H), 3.89 (dd, J=2.7 Hz, J=8.7 Hz, 1H), 3.72-3.63 (m, 2H),3.09-3.00 (m, 1H), 2.92-2.83 (m, 1H), 2.09 (d, J=3.99 Hz, 1H), 1.98-1.91(m, 1H), 1.69-1.66 (m, 2H), 1.52-1.46 (m, 1H); MS (MM) m/z 485.0 [M+H]⁺;HPLC purity>95 (% of ACU).

nn. Synthesis ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanesulfonamide(57)

i. Preparation of tert-butyl3-(cyclopropanesulfonamidomethyl)piperidine-1-carboxylate (1.65)

Same general procedure described for 1.2. MS (MM): m/z=218.1 [M-Boc]⁺.

ii. Preparation of N-(piperidin-3-ylmethyl)cyclopropanesulfonamide(1.66)

Same general procedure described for 1.3. MS (MM): m/z=219.1 [M+H]⁺.

iii. Preparation ofN-((1-(6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanesulfonamide(57)

Same general procedure described for compounds 1-14 above. Yield from1.66: 23%; ¹H NMR (300 MHz, DMSO-d₆): δ 8.67 (s, 1H), 8.21 (s, 1H), 8.06(d, J=8.7 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.17 (t, J=6 Hz, 1H), 4.41(d, J=12.9 Hz, 1H), 4.22 (d, J=13.2 Hz, 1H), 3.28 (d, J=12 Hz, 1H),3.07-2.89 (m, 3H), 2.57 (m, 1H), 1.91-1.80 (m, 3H), 1.68-1.59 (m, 1H),1.39-1.28 (m, 1H), 0.92-0.88 (m, 4H); MS (MM) m/z 415.1 [M+H]⁺; HPLCpurity>99 (% AUC).

oo. Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanesulfonamide(58)

Same procedure described for 57. Yield: 39%; ¹H NMR (300 MHz, DMSO-d6):δ 8.62 (s, 1H), 7.91-7.86 (dd, J=2.8 Hz, J=8.4 Hz, 1H), 7.78-7.71 (m,1H), 7.67-7.63 (m, 1H), 7.20 (t, J=6.3 Hz, 1H), 4.28 (d, J=12.3 Hz, 1H),4.13 (d, J=13.2 Hz, 1H), 3.18-3.10 (m, 1H), 3.01-2.86 (m, 3H), 2.59-2.54(m, 1H), 1.90-1.62 (m, 4H), 1.34-4.12 (m, 1H), 0.92-0.89 (m, 4H); MS(MM) m/z 365.1 [M+H]⁺; HPLC purity: >99 (% of AUC).

pp. Synthesis of4-(3-(cyclopropanesulfonamidomethyl)piperidin-1-yl)-6-fluoroquinazoline-7-carboxamide(59)

i. Preparation ofN-((1-(7-bromo-6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)-cyclopropanesulfonamide(1.67)

Same procedure described for 57.

ii. Preparation of4-(3-(cyclopropanesulfonamidomethyl)piperidin-1-yl)-6-fluoroquinazoline-7-carboxamide(59)

To a stirred solution of 1.67 (80 mg, 0.13 mmol) in DMF (5 mL) taken ina steel bomb was added silazane (0.08 mL, 0.40 mmol) and DIPEA (0.06 mL,0.40 mmol). Argon gas was purged and the reaction was degassed for about5 min. added Pd(OAc) (3 mg, 0.013 mmol), DPPP (10 mg). CO was filled upto 250 Psi, stirred at 100° C. for 4 h. Upon complete consumption ofstarting material, the reaction mixture was poured into water (20 mL),extracted with EtOAc (2×20 mL). The organic extracts were washed withwater (2×20 mL), brine (20 mL), dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (gradient elution 80-90% of EtOAc in hexanes)to afford 59 (15 mg, 21%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d6): δ 8.63 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=6.8 Hz, 1H), 7.83 (s,1H), 7.71 (d, J=11.2 Hz, 1H), 7.19 (t, J=5.6 Hz, 1H), 4.31 (d, J=14 Hz,1H), 4.17 (d, J=12.4 Hz, 1H), 3.20-3.15 (m, 1H), 2.98-2.91 (m, 3H),1.89-1.79 (m, 4H), 1.72-1.66 (m, 1H), 1.33-1.29 (m, 1H), 0.92-0.88 (m,4H); MS (MM) m/z 406.1 [M+H]⁺; HPLC purity>96 (% of AUC).

qq. Synthesis ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)morpholine-4-sulfonamide(60)

i. Preparation of (1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methanamine(1.68)

The amine 1.68 was prepared in two steps according to the same proceduredescribed for compounds 1-14 above. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s,1H), 7.95-7.78 (m, 4H), 7.76 (dd, J=9.7, 2.7 Hz, 1H), 4.34 (d, J=11.1Hz, 1H), 4.24 (d, J=13.1 Hz, 1H), 3.34 (tt, J=11.0, 2.9 Hz, 1H),3.24-3.12 (m, 3H), 2.82 (dh, J=25.3, 6.5 Hz, 1H), 1.96-1.78 (m, 2H),1.65 (s, 1H), 1.45-1.30 (m, 1H); FABMS (M+H) calculated for C₁₄H₇FN₄.Hwas 261.1510 found 261.1507; HPLC purity=100 (% of AUC), t_(R)=0.79minutes.

ii. Preparation ofN-((1-(6-fluoroquinazolin-4-yl)piperidin-3-yl)methyl)morpholine-4-sulfonamide(60)

Compound 60 was synthesized in 14% yield according the same proceduredescribed for 1.2. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.87 (dd,J=9.2, 5.6 Hz, 1H), 7.73 (ddd, J=9.2, 8.3, 2.8 Hz, 1H), 7.63 (dd, J=9.8,2.8 Hz, 1H), 7.44 (t, J=5.8 Hz, 1H), 4.25 (d, J=12.9 Hz, 1H), 4.11 (d,J=13.2 Hz, 1H), 3.61-3.54 (m, 4H), 3.13 (ddd, J=13.9, 11.4, 2.8 Hz, 1H),3.01-2.93 (m, 4H), 2.96-2.78 (m, 2H), 1.85 (d, J=12.7 Hz, 3H), 1.77 (s,1H), 1.65 (d, J=12.4 Hz, 1H), 1.30-1.11 (m, 1H).FABMS (M+H) calculatedfor C₁₈H₂₄FN₅O₃S.H was 410.1657 found 410.1653; HPLC purity>95 (% ofAUC), t_(R)=4.12 minutes.

iii. Preparation4-(3-(methylsulfonamidomethyl)piperidin-1-yl)-6-(trifluoromethyl)quinazoline1-oxide (61) andN-((1-(2-hydroxy-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(62)

rr. Synthesis of 61

To a solution of compound 11 (200 mg, 0.515 mmol) in CH₂C12 (10 ml), atrt under N₂ atmosphere, was added m-CPBA (410 mg, 1.545 mmol) and thereaction mixture was stirred at rt for 64 hr. The reaction mixture wasdiluted with CH₂C12 (20 mL) and the organic layer was washed withsat.NaHCO₃ solution (10 mL) and sat.NaSO₃ solution (10 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum to obtain the crude product. The product was purified bysilica-gel chromatography (15-20% CH₃₀H:CH₂Cl₂). Fractions containingthe product were combined and concentrated under vacuum. The obtainedsolids were washed with MTBE and filtered, dried under vacuum to obtain61 (60 mg, 0.148 mmol, 29%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.87 (s, 1H), 8.59 (d, J=8.8 Hz, 1H), 8.28-8.25 (m, 2H),7.10 (t, J=6.0 Hz, 1H), 4.19-4.16 (m, 1H), 4.04-4.01 (m, 1H), 3.30-3.24(m, 1H), 3.03-2.88 (m, 6H), 1.89-1.83 (m, 3H), 1.79-1.68 (m, 1H),1.34-1.26 (m, 1H). LCMS (ESI): m/z=405 [M+H]⁺. HPLC: >99% (AUC).

ss. Synthesis of 62

To a solution of 61 (150 mg, 0.371 mmol) in DCE (10 ml), at rt under N₂atmosphere was added Tosylchloride (141 mg, 0.742 mmol) and K₂CO₃ (103mg, 0.742 mmol) and the mixture was heated at 100° C. for 20 min undermicrowave condition. Concentrated the reaction mixture under vacuum andthe product was purified by silica-gel chromatography (10-12%CH₃₀H:CH₂Cl₂). Fractions containing the product were combined andconcentrated under vacuum. The obtained solids were washed with MTBE andfiltered, dried under vacuum to obtain 62 (63 mg, 0.156 mmol, 42% o) asan off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 11.25 (s, 1H),7.90-7.88 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.10 (t, J=6.0 Hz, 1H),4.25-4.22 (m, 1H), 4.11-4.08 (m, 1H), 3.23-3.18 (m, 1H), 2.97-2.82 (m,6H), 1.87-1.77 (m, 3H), 1.63-1.57 (m, 1H), 1.34-1.29 (m, 1H). LCMS(ESI): m/z=405 [M+H]⁺. HPLC: >99% (AUC).

iv. Preparation ofN-((1-(7-hydroxy-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(63)

tt. Preparation of 1.70

To a stirred solution of 1.69 (500 mg, 2.62 mmol) in DMF (10 ml) wasadded NBS (466 mg, 2.62 mmol) at rt and was stirred at same temperaturefor 3 h under argon. After 3 h; diluted the reaction mixture with water(50 mL) and the aqueous layer was extracted with EtOAc (100 mL). Theorganic layer was washed with water (3×100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum to give 1.70 (600 mg,2.22 mmol, 85%) as an light brown solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.55(s, 1H), 6.32 (s, 1H), 4.38 (brs, 2H), 3.82 (s, 3H).

uu. Preparation of 1.71

To a stirred solution of 1.70 (700 mg, 2.59 mmol) in DMF (10 ml) wasadded Zinc cyanide (457 mg, 3.89 mmol) and the mixture was purged withargon for 5 mins; then added Pd(PPh₃)₄ (300 mg, 0.259 mmol) and themixture was irradiated under microwave condition at 150° C. for 30 min.After 30 mins; cooled the reaction mixture to rt and was diluted withEtOAc (150 mL) and filtered through celite bed. The filtrate was washedwith H₂O (3×150 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The crude compound was purified by combiflashchromatography eluting with 25% EtOAc in Hexane to give 1.71 (500 mg,2.31 mmol, 89%, AMRI lot #AMR100625-36-1) as an off white solid. ¹H NMR(400 MHz, CDCl₃) δ: 7.58 (s, 1H), 6.24 (s, 1H), 4.74 (brs, 2H), 3.88 (s,3H).

vv. Preparation of 1.72

Formic acid (2.5 mL, 28.2 mmol) and sulfuric acid (2.5 mL, 20.28 mmol)was added to 1.71 (500 mg, 2.31 mmol) at rt and the mixture was stirredat 100° C. for 18 hr. After 18 hr; cooled the reaction mixture to rt andthe reaction mixture was slowly added to the crushed ice with stirring.The aqueous layer was basified with aq. NH₃ solution and the aqueouslayer was extracted with EtOAc (2×100 mL). The combined organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated under vacuumto give 1.72 (350 mg, 1.43 mmol, 62.0%) as an off white solid. ¹H NMR(400 MHz, DMSO-d₆) δ: 12.42 (s, 1H), 8.25 (s, 1H), 8.21 (s, 1H), 7.36(s, 1H), 4.02 (s, 3H).

ww. Preparation of 1.73

To the stirred suspension of 1.72 (100 mg, 0.410 mmol) in POCl₃ (0.382ml, 4.10 mmol) was added N,N-Dimethylaniline (0.123 ml, 1.024 mmol) atrt and was stirred at 120° C. for 4 hr under argon. After 4 hr, cooledthe reaction mixture to rt and the reaction mixture was concentratedunder vacuum. The crude residue was dissolved in CH₂C2 (50 mL) and theorganic layer was washed with water (50 mL). The organic layer was driedover anhydrous Na₂SO₄ and filtered and concentrated under vacuum. Thecrude residue was purified by combiflash chromatography eluting with 10%EtOAc in Hexane to give 1.73 (50 mg, 0.190 mmol, 46.5%) as an off whitesolid. ¹H NMR (400 MHz, CDCl₃) δ: 9.02 (s, 1H), 8.51 (s, 1H), 7.47 (s,1H), 4.09 (s, 3H).

xx. Preparation of 1.74

To a stirred solution of 1.73 (250 mg, 0.952 mmol) in NMP (10 mL) wereadded 6 (261 mg, 1.142 mmol) and DIPEA (0.499 ml, 2.86 mmol) at rt andwas stirred at rt for 30 min under argon. After 30 min; diluted thereaction mixture with water (50 mL) and extracted with EtOAc (50 mL).The organic layer was washed with water (3×100 mL) and dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum to afford 1.74(300 mg, 0.717 mmol, 75%) as a color less gummy solid. ¹H NMR (400 MHz,DMSO-d₆) δ: 8.59 (s, 1H), 8.11 (s, 1H), 7.38 (s, 1H), 7.09 (t, J=6.0 Hz,1H), 4.36-4.33 (m, 1H), 4.19-4.15 (m, 1H), 4.02 (s, 3H), 3.30-3.22 (m,1H), 2.99-2.85 (m, 6H), 1.89-1.79 (m, 3H), 1.68-1.59 (m, 1H), 1.35-1.27(m, 1H).

yy. Preparation of 63

Mixture of 1.74 (200 mg, 0.478 mmol) and pyridine hydrochloride (552 mg,4.78 mmol) was heated at 180° C. for 30 min under microwave. After 30min; cooled the reaction mixture and diluted with EtOAc (50 mL) andsaturated NaHCO₃ solution (10 mL). Separated the organic layer and theaqueous layer was extracted with EtOAc (50 mL), the combined organiclayer was dried over anhydrous NaSO₄, filtered and concentrated undervacuum. The crude residue was purified by mass triggered HPLC to give 63(31 mg, 0.077 mmol, 16.04%) as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ: 11.69 (brs, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.14-7.08 (m,2H), 4.31-4.28 (m, 1H), 4.15-4.11 (m, 1H), 3.24-3.18 (m, 1H), 2.97-2.85(m, 6H), 1.90-1.76 (m, 3H), 1.67-1.58 (m, 1H), 1.35-1.26 (m, 1H). LCMS(ESI): m/z=405 [M+H]⁺; HPLC: >99% (AUC).

v. Preparation ofN-((1-(8-hydroxy-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(64) andN-((1-(5-hydroxy-6-(trifluoromethyl)quinazolin-4-yl)piperidin-3-yl)methyl)methanesulfonamide(65)

Same procedure described for 63.

3. Characterization of Inhibitors of TXNIP Transcription

A list of compounds evaluated for their ability to inhibit TXNIPexpression is shown in Table 1 below.

TABLE 1 TXNIP % TXNIP % Inhibition at Inhibition at CC₅₀/72 h No.Structure 1.5 μM 12.5 μM (μM)  1

44 54 >100  2

13 61 >100  3

4 59 >100  4

24 16 >100  5

30 58 >100  6

29 43 >100  7

40 54 >100  8

0 7 >100  9

0 10 71 10

23 51 >100 11

45 53 56 11a

35 57 >100 12

0 13 >100 13

41 1 42 14

0 24 >100 15

0 20 73 16

0 33 >100 17

0 15 >100 18

10 10 >100 19

0 5 >100 20

19 30 >100 21

0 12 >100 22

15 34 >100 23

0 23 >100 24

20 20 >100 25

28 51 >100 26

2 28 >100 27

9 4 70 28

4 5 >100 29

39 66 >100 29a

35 55 >100 30

9 33 >100 31

17 82 67 32

21 62 65 33

29 68 68 34

56 61 33 35

38 64 41 36

0 34 35 37

0 24 >100 38

34 60 >100 39

7 28 >100 40

14 46 70 41

36 65 7 42

32 30 4 43

0 16 >100 44

4 22 >100 45

22 44 >100 46

0 55 >100 47

5 7 >100 48

3 26 >100 49

2 2 >100 50

2 18 >100 51

18 20 >100 52

4 5 >100 53

7 24 >100 54

19 53 17 55

29 41 7 56

19 30 17 57

33 67 43 58

15 65 57 59

5 5 >100 60

32 56 16 61

2 25 >100 62

20 20 >100 63

10 5 >100

K. References

-   Kenneth L and Thomas S. Analysis of relative gene expression data    using real-time quantitative PCR and the 2^(−ΔΔC) _(T) method.    Methods 2001; 25: 402-408.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A method for maintaining the body weight of amammal with diabetes or a diabetes related disorder associated withelevated TXNIP or elevated glucagon, comprising administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.
 2. The method of claim 1, wherein the compound has a structurerepresented by a formula:


3. The method of claim 2, wherein p is 0 or 1; R¹ is —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy¹; each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; and R^(8a) is hydrogen and R^(8b) is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl.
 4. The method of claim 2, wherein the compound has thefollowing structure:


5. The method of claim 1, wherein the compound has a structurerepresented by a formula selected from:


6. The method of claim 1, wherein p is
 1. 7. A method for lowering liverand serum lipid levels in a mammal, comprising administering to themammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.
 8. The method of claim 7, wherein the compound has a structurerepresented by a formula:


9. The method of claim 8, wherein p is 0 or 1; R¹ is —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy¹; each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; and R^(8a) is hydrogen and R^(8b) is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl.
 10. The method of claim 8, wherein the compound has thefollowing structure:


11. The method of claim 7, wherein the compound has a structurerepresented by a formula selected from:


12. The method of claim 7, wherein p is
 1. 13. A method for lowering thelevels of non-esterified fatty acids and of triglycerides in the serumof a mammal, comprising administering to the mammal a therapeuticallyeffective amount of at least one compound having a structure representedby a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.
 14. The method of claim 13, wherein the compound has astructure represented by a formula:


15. The method of claim 14, wherein p is 0 or 1; R¹ is —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy¹; each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; and R^(8a) is hydrogen and R^(8b) is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl.
 16. The method of claim 14, wherein the compound hasthe following structure:


17. The method of claim 13, wherein the compound has a structurerepresented by a formula selected from:


18. The method of claim 13, wherein p is
 1. 19. A method for inhibitingalpha cell glucagon secretion in a mammal, comprising administering tothe mammal a therapeutically effective amount of at least one compoundhaving a structure represented by a formula selected from:

wherein n is 0, 1, or 2; wherein p is 0, 1, 2, 3, or 4; wherein q is 0or 1; wherein R¹ is —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —(C1-C4 alkyl)(C1-C4 alkoxy), —(C1-C4 alkyl)CO₂H, or Cy¹;wherein Cy¹, when present, is C3-C6 cycloalkyl, C2-C5 heterocycloalkyl,or aryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R² ishydrogen or C1-C4 alkyl, or wherein each of R¹ and R² are covalentlybonded together and, together with the intermediate atoms, comprise a 3-to 6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R³ is hydrogen or C1-C4 alkyl, or wherein each ofR¹ and R³ are covalently bonded together and, together with theintermediate atoms, comprise a 5- to 7-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; wherein R⁴ is hydrogen,halogen, —NH₂, —OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or Cy²; wherein Cy², when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein each of R^(5a), R^(5b), R^(5c), andR^(5d) is independently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl,C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, —CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂,—NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), or Cy³; wherein Cy³, when present, isC3-C6 cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,—OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino; wherein A is O, NR^(6a), or CHR^(6b);wherein R^(6a) is hydrogen or C1-C4 alkyl; and wherein R^(6b) ishydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, or —CO₂H; wherein R⁷ is hydrogen, halogen,—OH, C1-C4 alkyl, C1-C4 haloalkyl, or C1-C4 alkoxy; wherein eachoccurrence of R^(8a) and R^(8b), when present, is independentlyhydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl, or —CO₂H; or wherein pis 1 and each of R^(8a) and R^(8b) together comprise ═O; and wherein R⁹is hydrogen, C1-C4 alkyl, or Cy⁴, wherein Cy⁴, when present, is C3-C6cycloalkyl, C2-C5 heterocycloalkyl, or aryl, and is substituted with 0,1, 2, or 3 groups independently selected from halogen, —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable saltthereof.
 20. The method of claim 19, wherein the compound has astructure represented by a formula:


21. The method of claim 20, wherein p is 0 or 1; R¹ is —NH₂, —OH, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, or Cy¹; each of R^(5a), R^(5b), R^(5c), and R^(5d) isindependently hydrogen, halogen, —NH₂, —CN, —OH, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,—CO₂(C1-C4 alkyl), —CO₂H, —CO₂NH₂, —NHC(O)Cy³, —NHC(O)(C1-C4 alkyl), orCy³; and R^(8a) is hydrogen and R^(8b) is hydrogen, C1-C4 alkyl, orC1-C4 haloalkyl.
 22. The method of claim 20, wherein the compound hasthe following structure:


23. The method of claim 19, wherein the compound has a structurerepresented by a formula selected from:


24. The method of claim 19, wherein p is 1.